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Journal of Clinical Bioinformatics

Open Access

A ceRNA analysis on LMNA gene focusing on the Hutchinson-Gilford progeria syndrome

Journal of Clinical Bioinformatics20133:2

https://doi.org/10.1186/2043-9113-3-2

Received: 10 October 2012

Accepted: 7 January 2013

Published: 14 January 2013

Abstract

Background

Hutchinson-Gilford progeria syndrome is a rare dominant human disease of genetic origin. The average life expectancy is about 20 years, patients’ life quality is still very poor and no efficient therapy has yet been developed. It is caused by mutation of the LMNA gene, which results in accumulation in the nuclear membrane of a particular splicing form of Lamin-A called progerin. The mechanism by which progerin perturbs cellular homeostasis and leads to the symptoms is still under debate.

Micro-RNAs are able to negatively regulate transcription by coupling with the 3’ UnTranslated Region of messenger RNAs. Several Micro-RNAs recognize the same 3’ UnTranslated Region and each Micro-RNA can recognize multiple 3’ UnTranslated Regions of different messenger RNAs. When different messenger RNAs are co-regulated via a similar panel of micro-RNAs, these messengers are called Competing Endogenous RNAs, or ceRNAs.

The 3’ UnTranslated Region of the longest LMNA transcript was analysed looking for its ceRNAs. The aim of this study was to search for candidate genes and gene ontology functions possibly influenced by LMNA mutations that may exert a role in progeria development.

Results

11 miRNAs were isolated as potential LMNA regulators. By computational analysis, the miRNAs pointed to 17 putative LMNA ceRNAs. Gene ontology analysis of isolated ceRNAs showed an enrichment in RNA interference and control of cell cycle functions.

Conclusion

This study isolated novel genes and functions potentially involved in LMNA network of regulation that could be involved in laminopathies such as the Hutchinson-Gilford progeria syndrome.

Keywords

CeRNAHutchinson-GilfordProgeria LMNA Lamin-A3’ UTRMiRNA

Background

Lamins are intermediate filament proteins associated with the inner nuclear membrane and are structural components of the nuclear lamina. Interestingly, they can also be found in the nucleoplasm, where they might have regulatory functions that are still poorly investigated [13]. Lamins are structural components of the nuclear membrane, but they are also essential for many nuclear functions [1, 3]. Lamins can bind to specific DNA sequences, chromatin modifications, and chromatin associated proteins or complexes either directly or through lamin-interacting proteins [14]. It has been reported that lamin functions are involved in transcriptional regulation, DNA replication and repair, epigenetic modifications, chromatin remodelling, and transition between euchromatin and heterochromatin conformation [1, 3, 4]. Lamins are present in almost all pluricellular organisms, with the exception of plants, and are usually absent in unicellular organisms [5, 6]. Generally, lamins are divided into types A and B. In humans, A-type lamins are divided into A and C lamins, both derived by alternative splicing from the LMNA gene [5, 6]. Interestingly, in humans, stem cells and undifferentiated cells seem to lack Lamin-A and Lamin-C. In this perspective, LMNA expressed lamins behave as markers of differentiation [7].

The Hutchinson-Gilford progeria Syndrome (HGPS) is a very rare human disease of genetic origin that leads to very severe premature ageing. HGPS is caused by several mutations in the LMNA gene, the most common of which is the point mutation C1824T, which leads to the accumulation in the nuclear membrane of a rare splicing form of the Lamin-A called “progerin”, and alterations in nuclear shape and structure like the typical nuclear bubbling, the cytological hallmark of HGPS [8]. The accumulation of progerin is due to the impossibility of physiological cleavage of the mature wild type Lamin-A protein. Usually, Lamin-A is farnesylated and incorporated into the nuclear membrane, and later is cleaved and released from the nuclear lamina. The classical mutation in HGPS enhances the activity of a cryptic splicing site that increases the production of progerin and lessens the production of Lamin-A [8, 9], acting as a dominant mutation. Progerin lacks the cleavage site, so the protein is farnesylated and loaded into the membrane but cannot be removed efficiently any more, so it accumulates [8, 10]. It is to be noted that progerin physiologically accumulates in the cells of ageing individuals, with a positive correlation with chronological age [911]. HGPS affected individuals have a life expectancy of about twenty years and a very poor quality of life [12]. No efficient healing therapy has yet been developed and the main focus of current pharmacological strategies is on farnesylation inhibitors that lessen the progerin load in the nuclear membrane [10]. Though an amelioration of the symptoms has been reported, farnesylation inhibitors have not led to a definitive solution [10]. The mechanism by which progerin accumulation perturbs cellular homeostasis and leads to the symptoms is still under debate [10]. The aim of this study was to look for candidate genes and gene ontology functions influenced by LMNA mutations that in turn may have a role in progeria development.

The ceRNA (competing endogenous RNAs) hypothesis is based on the rationale that RNA molecules can regulate one another via microRNAs (miRNAs or miRs) and that messengers RNAs (mRNAs) can be positively co-regulated if they share miRNA target sequences amongst their 3’UnTranslated regions (3’UTR), because there is a limited amount of miRNAs within each cell, and each mRNA can act as a quencher for shared miRNAs [13]. Following this rationale, genes whose mRNAs share miRNAs targets in their 3’UTRs might be post-transcriptionally co-regulated. For a more exhaustive description of ceRNA rationale see [2, 13]. The study reported on here follows another study [2] on LMNA interactome. This study focuses on an analysis of the Lamin-A ceRNAs network of interactions.

Methods

Using the miRWalk [14] database for predicted gene targets, miRNAs of a minimum of 7 matching nucleotides on the longest human LMNA transcript 3’UTR with a maximum p value of 0.05 were isolated. The settings chosen were the standard settings for the software used [14]. The 3’UTR analysed is the same in Lamin-A and progerin transcripts; the 3’ UTR of Lamin-C is shorter and different, and not included in this study. The work was performed on predicted gene targets because there are no validated targets reported for LMNA transcripts in the miRWalk database. The miRNAs considered as putatively recognizing the 3’UTR of the LMNA mRNA were 11 and reported in Table 1. Table 1 also shows a mimiRNA analysis [15] of the compared expression profiles of LMNA and each miRNA in human tissues and cell lines collected in the database. The set of miRNAs in Table 1 was inserted into the miRWalk [14] MicroRNA validated targets analysing tool to discover any human gene mRNA 3’UTR that has been reported to have been recognized by any of them. The genes isolated and the related bait miRNAs are shown in Table 2. The genes collected were organized in a hierarchical order for the number of validated microRNA hits (Table 3). The more microRNAs are shared between the 3’UTR of the longest LMNA transcript and the 3’UTRs of the candidate genes, the higher the possibility that the gene transcripts can act as LMNA ceRNAs. The maximum number of hits is 5. Genes that share in their transcripts 3 to 5 validated microRNAs with the predicted microRNAs with the 3’UTR of the longest LMNA transcript were arbitrarily considered as potential ceRNAs for further analyses. 17 genes have these characteristics out of a total of 335. These 17 genes were analysed using the GeneMANIA [16] tool that helps to predict the functions of a set of genes and to predict in which Gene Ontology (GO) functions the set of genes might be involved. The results are reported in Table 4. Table 4 also shows the GO functions from the ones with the lowest False Discovery Rate (FDR) till a FDR < 0.1. All analyses were updated to September 13th 2012.
Table 1

Predicted miRNAs that hit LMNA 3'UTR mRNA

Gene name

RefSeqID

MicroRNA

StemLoop ID

Seed length

Start

Sequence

End

Region

Pvalue

mimiRNA correlation coefficient

mimiRNA Pvalue

LMNA

NM_170707

hsa-miR-539

hsa-mir-539

10

2490

GGAGAAAUUA

2481

3 UTR

0.0010

−0.499

0.081

LMNA

NM_170707

hsa-miR-671-5p

hsa-mir-671

10

2553

AGGAAGCCCU

2544

3 UTR

0.0010

−0.212

0.093

LMNA

NM_170707

hsa-miR-214

hsa-mir-214

9

2780

ACAGCAGGC

2772

3 UTR

0.0038

0.131

0.37

LMNA

NM_170707

hsa-miR-9

hsa-mir-9-1

9

2544

UCUUUGGUU

2536

3 UTR

0.0038

−0.133

0.32

LMNA

NM_170707

hsa-miR-637

hsa-mir-637

9

2828

ACUGGGGGC

2820

3 UTR

0.0038

−0.675

0.066

LMNA

NM_170707

hsa-miR-298

hsa-mir-298

9

2600

AGCAGAAGC

2592

3 UTR

0.0038

no results

no results

LMNA

NM_170707

hsa-miR-34a

hsa-mir-34a

8

2709

UGGCAGUG

2702

3 UTR

0.0151

0.26

0.0071

LMNA

NM_170707

hsa-miR-342-5p

hsa-mir-342

8

3183

AGGGGUGC

3176

3 UTR

0.0151

−0.212

0.093

LMNA

NM_170707

hsa-miR-449a

hsa-mir-449a

8

2709

UGGCAGUG

2702

3 UTR

0.0151

no results

no results

LMNA

NM_170707

hsa-miR-532-3p

hsa-mir-532

8

2933

CCUCCCAC

2926

3 UTR

0.0151

0.851

0.032

LMNA

NM_170707

hsa-miR-608

hsa-mir-608

8

2838

AGGGGUGG

2831

3 UTR

0.0151

−0.757

0.0138

Table 2

miRNAs that hit LMNA 3’UTR: their validated targets

MicroRNA name

StemLoopName

miR_Chr.

Gene name

EntrezID

Pubmed ID

hsa-miR-9

hsa-mir-9-1

1

PRDM1

639

20966935

hsa-miR-9

hsa-mir-9-1

1

TP73

7161

18842901

hsa-miR-9

hsa-mir-9-1

1

MAPK3

5595

19958814

hsa-miR-9

hsa-mir-9-1

1

RAB34

83871

19531230

hsa-miR-9

hsa-mir-9-3

15

TP53

7157

19549897

hsa-miR-9

hsa-mir-9-1

1

TLR4

7099

19289835

hsa-miR-9

hsa-mir-9-1

1

SLC27A4

10999

20634564

hsa-miR-9

hsa-mir-9-1

1

DICER1

23405

18442408

hsa-miR-9

hsa-mir-9-1

1

NPAT

4863

18997113

hsa-miR-9

hsa-mir-9-1

1

FZR1

51343

20173740

hsa-miR-9

hsa-mir-9-1

1

CDC14A

8556

19956200

hsa-miR-9

hsa-mir-9-1

1

HRB

3267

16831872

hsa-miR-9

hsa-mir-9-1

1

FOXP1

27086

21248104

hsa-miR-9

hsa-mir-9-1

1

SOX2

6657

20947512

hsa-miR-9

hsa-mir-9-1

1

CDK6

1021

18768788

hsa-miR-9

hsa-mir-9-1

1

CDKN1A

1026

19956200

hsa-miR-9

hsa-mir-9-1

1

HDAC9

9734

19521961

hsa-miR-9

hsa-mir-9-1

1

C1orf61

10485

19289835

hsa-miR-9

hsa-mir-9-1

1

SIRT1

23411

20634564

hsa-miR-9

hsa-mir-9-1

1

RNASEN

29102

18442408

hsa-miR-9

hsa-mir-9-1

1

DICER1

23405

18997113

hsa-miR-9

hsa-mir-9-1

1

CDH1

999

20173740

hsa-miR-9

hsa-mir-9-1

1

CCNE1

898

19956200

hsa-miR-9

hsa-mir-9-1

1

EDG6

8698

16831872

hsa-miR-9

hsa-mir-9-1

1

FGF8

2253

21238922

hsa-miR-9

hsa-mir-9-1

1

LIN28

79727

20947512

hsa-miR-9

hsa-mir-9-1

1

E2F3

1871

18768788

hsa-miR-9

hsa-mir-9-1

1

CHEK1

1111

19956200

hsa-miR-9

hsa-mir-9-1

1

REST

5978

19458943

hsa-miR-9

hsa-mir-9-1

1

KRAS

3845

19137007

hsa-miR-9

hsa-mir-9-1

1

CREB1

1385

20624818

hsa-miR-9

hsa-mir-9-1

1

BACE1

23621

18434550

hsa-miR-9

hsa-mir-9-1

1

ELAVL2

1993

21368052

hsa-miR-9

hsa-mir-9-1

1

ELSPBP1

64100

18997113

hsa-miR-9

hsa-mir-9-1

1

BRCA1

672

20167074

hsa-miR-9

hsa-mir-9-1

1

CCNF

899

19956200

hsa-miR-9

hsa-mir-9-1

1

TRPM3

80036

16736490

hsa-miR-9

hsa-mir-9-1

1

TP53

7157

21238922

hsa-miR-9

hsa-mir-9-1

1

E2F1

1869

20930934

hsa-miR-9

hsa-mir-9-1

1

MYC

4609

18768788

hsa-miR-9

hsa-mir-9-1

1

ETS1

2113

19956200

hsa-miR-9

hsa-mir-9-1

1

MPI

4351

19406203

hsa-miR-9

hsa-mir-9-1

1

MAPK3

5595

19137007

hsa-miR-9

hsa-mir-9-1

1

REST

5978

20624818

hsa-miR-9

hsa-mir-9-1

1

CDKN2D

1032

18410378

hsa-miR-9

hsa-mir-9-1

1

ELAVL1

1994

21368052

hsa-miR-9

hsa-mir-9-1

1

PMP22

5376

18987208

hsa-miR-9

hsa-mir-9-1

1

NFKB1

4790

20102618

hsa-miR-9

hsa-mir-9-1

1

CCNE2

9134

19956200

hsa-miR-9

hsa-mir-9-1

1

COL9A1

1297

16718610

hsa-miR-9

hsa-mir-9-1

1

SLC22A3

6581

21109969

hsa-miR-9

hsa-mir-9-1

1

MYC

4609

20930934

hsa-miR-9

hsa-mir-9-1

1

TGIF2

60436

18768788

hsa-miR-9

hsa-mir-9-1

1

ATF6

22926

19956200

hsa-miR-9

hsa-mir-9-1

1

CD46

4179

19330006

hsa-miR-9

hsa-mir-9-1

1

REST

5978

19137007

hsa-miR-9

hsa-mir-9-1

1

IGFALS

3483

20616011

hsa-miR-9

hsa-mir-9-1

1

DNMT1

1786

18314617

hsa-miR-9

hsa-mir-9-1

1

FOXG1

2290

21368052

hsa-miR-9

hsa-mir-9-1

1

PXMP2

5827

18987208

hsa-miR-9

hsa-mir-9-1

1

FOXO1

2308

20028871

hsa-miR-9

hsa-mir-9-1

1

KIF23

9493

19956200

hsa-miR-9

hsa-mir-9-1

1

SOAT1

6646

16357340

hsa-miR-9

hsa-mir-9-1

1

SOX2

6657

21109969

hsa-miR-9

hsa-mir-9-1

1

CEBPA

1050

20806079

hsa-miR-9

hsa-mir-9-1

1

PRDM1

639

18583325

hsa-miR-9

hsa-mir-9-1

1

EIF2C1

26523

19956200

hsa-miR-9

hsa-mir-9-1

1

NR2E1

7101

19330006

hsa-miR-9

hsa-mir-9-1

1

REST

5978

19118166

hsa-miR-9

hsa-mir-9-1

1

STMN1

3925

20616011

hsa-miR-9

hsa-mir-9-1

1

ROS1

6098

17629564

hsa-miR-9

hsa-mir-9-1

1

MEIS2

4212

21368052

hsa-miR-9

hsa-mir-9-1

1

ERBB2

2064

18973228

hsa-miR-9

hsa-mir-9-1

1

BDNF

627

19958814

hsa-miR-9

hsa-mir-9-1

1

CDC25A

993

19956200

hsa-miR-9

hsa-mir-9-1

1

STAT3

6774

21385897

hsa-miR-9

hsa-mir-9-1

1

PROM1

8842

21109969

hsa-miR-9

hsa-mir-9-1

1

CEBPB

1051

20806079

hsa-miR-9

hsa-mir-9-1

1

ATN1

1822

18583325

hsa-miR-9

hsa-mir-9-1

1

PAK3

5063

19956200

hsa-miR-9

hsa-mir-9-1

1

IFNG

3458

19289835

hsa-miR-9

hsa-mir-9-1

1

RCOR1

23186

19118166

hsa-miR-9

hsa-mir-9-1

1

STMN1

3925

20362537

hsa-miR-9

hsa-mir-9-1

1

FMR1

2332

17379214

hsa-miR-9

hsa-mir-9-1

1

PAX6

5080

21368052

hsa-miR-9

hsa-mir-9-1

1

MYC

4609

18973228

hsa-miR-9

hsa-mir-9-1

1

EPHB2

2048

19958814

hsa-miR-9

hsa-mir-9-1

1

NFKB1

4790

19702828

hsa-miR-9

hsa-mir-9-1

1

CBX7

23492

18686603

hsa-miR-9

hsa-mir-9-1

1

APC

324

21060828

hsa-miR-9

hsa-mir-9-1

1

DDIT3

1649

20806079

hsa-miR-9

hsa-mir-9-1

1

COMP

1311

18573151

hsa-miR-9

hsa-mir-9-1

1

ANLN

54443

19956200

hsa-miR-9

hsa-mir-9-1

1

IL1B

3553

19289835

hsa-miR-9

hsa-mir-9-1

1

BCL2

596

19118166

hsa-miR-9

hsa-mir-9-1

1

MYC

4609

20173743

hsa-miR-9

hsa-mir-9-1

1

FOXG1

2290

17260156

hsa-miR-9

hsa-mir-9-1

1

NR2E1

7101

21368052

hsa-miR-9

hsa-mir-9-1

1

NTRK3

4916

18973228

hsa-miR-9

hsa-mir-9-1

1

GRIA1

2890

19958814

hsa-miR-9

hsa-mir-9-1

1

FZR1

51343

19572217

hsa-miR-9

hsa-mir-9-2

5

FRAP1

2475

20022054

hsa-miR-9

hsa-mir-9-1

1

RASSF1

11186

21060828

hsa-miR-9

hsa-mir-9-1

1

MYD88

4615

19289835

hsa-miR-9

hsa-mir-9-1

1

HMOX1

3162

20806079

hsa-miR-9

hsa-mir-9-1

1

GHRHR

2692

18573151

hsa-miR-9

hsa-mir-9-1

1

POU2F2

5452

19956200

hsa-miR-9

hsa-mir-9-1

1

RUNX1

861

19114653

hsa-miR-9

hsa-mir-9-1

1

MYC

4609

20173740

hsa-miR-9

hsa-mir-9-1

1

CREB1

1385

17002790

hsa-miR-9

hsa-mir-9-1

1

SLC7A5

8140

21368052

hsa-miR-9

hsa-mir-9-1

1

FOXG1

2290

18842901

hsa-miR-9

hsa-mir-9-1

1

GRIN2A

2903

19958814

hsa-miR-9

hsa-mir-9-1

1

CDH1

999

19572217

hsa-miR-9

hsa-mir-9-2

5

VEGFA

7422

20022054

hsa-miR-9

hsa-mir-9-1

1

FZR1

51343

21060828

hsa-miR-9

hsa-mir-9-1

1

NFKB1

4790

19289835

hsa-miR-9

hsa-mir-9-1

1

ROS1

6098

20806079

hsa-miR-9

hsa-mir-9-1

1

CHRD

8646

18573151

hsa-miR-9

hsa-mir-9-1

1

BCL6

604

19956200

hsa-miR-9

hsa-mir-9-1

1

IL1B

3553

19008124

hsa-miR-9

hsa-mir-9-1

1

MYCN

4613

20173740

hsa-miR-9

hsa-mir-9-1

1

REST

5978

17002790

hsa-miR-9

hsa-mir-9-1

1

GSX2

170825

21368052

hsa-miR-9

hsa-mir-9-1

1

BCL6

604

20966935

hsa-miR-9

hsa-mir-9-1

1

NEUROD1

4760

18842901

hsa-miR-9

hsa-mir-9-1

1

GRIN2B

2904

19958814

hsa-miR-9

hsa-mir-9-1

1

GRB2

2885

19531230

hsa-miR-9

hsa-mir-9-2

5

LARP6

55323

20022054

hsa-miR-9

hsa-mir-9-1

1

TLR2

7097

19289835

hsa-miR-9

hsa-mir-9-1

1

RPE

6120

20806079

hsa-miR-9

hsa-mir-9-1

1

NOG

9241

18573151

hsa-miR-9

hsa-mir-9-1

1

WEE1

7465

19956200

hsa-miR-9

hsa-mir-9-1

1

MMP13

4322

19008124

hsa-miR-9

hsa-mir-9-1

1

VEGFA

7422

20173740

hsa-miR-9

hsa-mir-9-1

1

ZNF828

283489

17002790

hsa-miR-9

hsa-mir-9-1

1

SIRT1

23411

21288303

hsa-miR-671-5p

hsa-mir-671

7

FASN

2194

20497147

hsa-miR-671-5p

hsa-mir-671

7

IGF1

3479

20497147

hsa-miR-671-5p

hsa-mir-671

7

IL6

3569

20497147

hsa-miR-671-5p

hsa-mir-671

7

NFKB1

4790

20497147

hsa-miR-671-5p

hsa-mir-671

7

RELB

5971

20497147

hsa-miR-608

hsa-mir-608

10

EIF2C1

26523

19851984

hsa-miR-608

hsa-mir-608

10

RNASEN

29102

19138993

hsa-miR-608

hsa-mir-608

10

XPO5

57510

20732906

hsa-miR-608

hsa-mir-608

10

EIF2C2

27161

19851984

hsa-miR-608

hsa-mir-608

10

DGCR8

54487

19138993

hsa-miR-608

hsa-mir-608

10

TARBP2

6895

20732906

hsa-miR-608

hsa-mir-608

10

GEMIN4

50628

19851984

hsa-miR-608

hsa-mir-608

10

XPO5

57510

19138993

hsa-miR-608

hsa-mir-608

10

PIWIL1

9271

20732906

hsa-miR-608

hsa-mir-608

10

DGCR8

54487

19851984

hsa-miR-608

hsa-mir-608

10

TARBP2

6895

19138993

hsa-miR-608

hsa-mir-608

10

DICER1

23405

16505370

hsa-miR-608

hsa-mir-608

10

C1orf183

55924

19851984

hsa-miR-608

hsa-mir-608

10

PIWIL1

9271

19138993

hsa-miR-608

hsa-mir-608

10

IL6

3569

21209110

hsa-miR-608

hsa-mir-608

10

MAP3K12

7786

19851984

hsa-miR-608

hsa-mir-608

10

DICER1

23405

20732906

hsa-miR-608

hsa-mir-608

10

SCPEP1

59342

21209110

hsa-miR-608

hsa-mir-608

10

GEMIN4

50628

19138993

hsa-miR-608

hsa-mir-608

10

RNASEN

29102

20732906

hsa-miR-608

hsa-mir-608

10

CD44

960

21149267

hsa-miR-608

hsa-mir-608

10

DDX20

11218

19138993

hsa-miR-608

hsa-mir-608

10

GEMIN4

50628

20732906

hsa-miR-608

hsa-mir-608

10

CDC42

998

21149267

hsa-miR-608

hsa-mir-608

10

DICER1

23405

19138993

hsa-miR-608

hsa-mir-608

10

DDX20

11218

20732906

hsa-miR-608

hsa-mir-608

10

DICER1

23405

19851984

hsa-miR-608

hsa-mir-608

10

EIF2C1

26523

19138993

hsa-miR-608

hsa-mir-608

10

EIF2C1

26523

20732906

hsa-miR-608

hsa-mir-608

10

HUWE1

10075

19851984

hsa-miR-608

hsa-mir-608

10

EIF2C2

27161

19138993

hsa-miR-608

hsa-mir-608

10

DGCR8

54487

20732906

hsa-miR-539

hsa-mir-539

14

KIT

3815

21273305

hsa-miR-539

hsa-mir-539

14

MITF

4286

21273305

hsa-miR-539

hsa-mir-539

14

HLCS

3141

20592104

hsa-miR-539

hsa-mir-539

14

LRPAP1

4043

16973894

hsa-miR-532-3p

hsa-mir-532

X

RUNX3

864

19336521

hsa-miR-532-3p

hsa-mir-532

X

CDKN2D

1032

19771204

hsa-miR-449a

hsa-mir-449a

5

TP53

7157

20948989

hsa-miR-449a

hsa-mir-449a

5

WISP2

8839

19351815

hsa-miR-449a

hsa-mir-449a

5

MAPK8

5599

20859756

hsa-miR-449a

hsa-mir-449a

5

HDAC9

9734

19252524

hsa-miR-449a

hsa-mir-449a

5

C9orf127

51754

20859756

hsa-miR-449a

hsa-mir-449a

5

HDAC1

3065

19252524

hsa-miR-449a

hsa-mir-449a

5

RBBP6

5930

20485546

hsa-miR-449a

hsa-mir-449a

5

E2F5

1875

19056356

hsa-miR-449a

hsa-mir-449a

5

TP53

7157

20485546

hsa-miR-449a

hsa-mir-449a

5

LAMC2

3918

19056356

hsa-miR-449a

hsa-mir-449a

5

TP73

7161

20485546

hsa-miR-449a

hsa-mir-449a

5

LMX1A

4009

19056356

hsa-miR-449a

hsa-mir-449a

5

CKAP4

10970

20485546

hsa-miR-449a

hsa-mir-449a

5

ELSPBP1

64100

19056356

hsa-miR-449a

hsa-mir-449a

5

DGCR8

54487

20485546

hsa-miR-449a

hsa-mir-449a

5

CDK6

1021

19833767

hsa-miR-449a

hsa-mir-449a

5

SERPINE1

5054

21375729

hsa-miR-449a

hsa-mir-449a

5

SERPINE1

5054

20356416

hsa-miR-449a

hsa-mir-449a

5

CDC25A

993

19833767

hsa-miR-449a

hsa-mir-449a

5

CCND1

595

20948989

hsa-miR-449a

hsa-mir-449a

5

PRKAR1A

5573

19351815

hsa-miR-449a

hsa-mir-449a

5

HDAC1

3065

20948989

hsa-miR-449a

hsa-mir-449a

5

WNT1

7471

19351815

hsa-miR-34a*

hsa-mir-34a

1

CDKN2A

1029

19396864

hsa-miR-34a*

hsa-mir-34a

1

HGF

3082

19396864

hsa-miR-34a*

hsa-mir-34a

1

JUN

3725

19396864

hsa-miR-34a*

hsa-mir-34a

1

NF2

4771

19396864

hsa-miR-34a*

hsa-mir-34a

1

PDGFA

5154

19396864

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

21225432

hsa-miR-34a

hsa-mir-34a

1

COL2A1

1280

20675358

hsa-miR-34a

hsa-mir-34a

1

ATP6V1B2

526

20144220

hsa-miR-34a

hsa-mir-34a

1

E2F3

1871

19167416

hsa-miR-34a

hsa-mir-34a

1

CD44

960

19714243

hsa-miR-34a

hsa-mir-34a

1

HOXA5

3202

14697198

hsa-miR-34a

hsa-mir-34a

1

TIMM8A

1678

21051724

hsa-miR-34a

hsa-mir-34a

1

E2F3

1871

20428827

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19921694

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

18755897

hsa-miR-34a

hsa-mir-34a

1

JAK2

3717

17976522

hsa-miR-34a

hsa-mir-34a

1

CREB1

1385

19461653

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

17554337

hsa-miR-34a

hsa-mir-34a

1

CCNE2

9134

19461653

hsa-miR-34a

hsa-mir-34a

1

MGST1

4257

21216258

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20598588

hsa-miR-34a

hsa-mir-34a

1

ZEB1

6935

20037478

hsa-miR-34a

hsa-mir-34a

1

AKT1

207

19029026

hsa-miR-34a

hsa-mir-34a

1

HMGA2

8091

18803879

hsa-miR-34a

hsa-mir-34a

1

VEGFA

7422

18320040

hsa-miR-34a

hsa-mir-34a

1

KRAS

3845

20978195

hsa-miR-34a

hsa-mir-34a

1

SLC12A1

6557

20420713

hsa-miR-34a

hsa-mir-34a

1

JAG1

182

19398721

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20881002

hsa-miR-34a

hsa-mir-34a

1

MET

4233

18834857

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

21182263

hsa-miR-34a

hsa-mir-34a

1

SMARCA5

8467

20439489

hsa-miR-34a

hsa-mir-34a

1

BNIP3L

665

20018759

hsa-miR-34a

hsa-mir-34a

1

CCND1

595

18823940

hsa-miR-34a

hsa-mir-34a

1

MDM2

4193

18677110

hsa-miR-34a

hsa-mir-34a

1

CCND3

896

18406353

hsa-miR-34a

hsa-mir-34a

1

CDC25A

993

21321636

hsa-miR-34a

hsa-mir-34a

1

SCPEP1

59342

20883704

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20185821

hsa-miR-34a

hsa-mir-34a

1

VEGFA

7422

19293812

hsa-miR-34a

hsa-mir-34a

1

ARCN1

372

21224215

hsa-miR-34a

hsa-mir-34a

1

IL1B

3553

20675358

hsa-miR-34a

hsa-mir-34a

1

IFNG

3458

20130213

hsa-miR-34a

hsa-mir-34a

1

MITF

4286

19167416

hsa-miR-34a

hsa-mir-34a

1

NOTCH1

4851

19714243

hsa-miR-34a

hsa-mir-34a

1

MECP2

4204

14697198

hsa-miR-34a

hsa-mir-34a

1

MET

4233

21051724

hsa-miR-34a

hsa-mir-34a

1

RB1

5925

20428827

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19890883

hsa-miR-34a

hsa-mir-34a

1

BBC3

27113

18755897

hsa-miR-34a

hsa-mir-34a

1

MYB

4602

17976522

hsa-miR-34a

hsa-mir-34a

1

E2F3

1871

19461653

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

17554199

hsa-miR-34a

hsa-mir-34a

1

CDC25C

995

19461653

hsa-miR-34a

hsa-mir-34a

1

NFE2L2

4780

21216258

hsa-miR-34a

hsa-mir-34a

1

FOXP1

27086

20598588

hsa-miR-34a

hsa-mir-34a

1

FRAP1

2475

20018759

hsa-miR-34a

hsa-mir-34a

1

TIMM8A

1678

19029026

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

17914404

hsa-miR-34a

hsa-mir-34a

1

HNF4A

3172

20018894

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20978195

hsa-miR-34a

hsa-mir-34a

1

TCF21

6943

20420713

hsa-miR-34a

hsa-mir-34a

1

NDUFA2

4695

19398721

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

20466628

hsa-miR-34a

hsa-mir-34a

1

RGS3

5998

18834857

hsa-miR-34a

hsa-mir-34a

1

YY1

7528

21182263

hsa-miR-34a

hsa-mir-34a

1

JARID1B

10765

20439489

hsa-miR-34a

hsa-mir-34a

1

BRAP

8315

20018759

hsa-miR-34a

hsa-mir-34a

1

E2F3

1871

18823940

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

18677110

hsa-miR-34a

hsa-mir-34a

1

CDC25A

993

18406353

hsa-miR-34a

hsa-mir-34a

1

CDK6

1021

21321636

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20868483

hsa-miR-34a

hsa-mir-34a

1

NR1H4

9971

20185821

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19258450

hsa-miR-34a

hsa-mir-34a

1

E2F5

1875

19461653

hsa-miR-34a

hsa-mir-34a

1

HDAC2

3066

21224215

hsa-miR-34a

hsa-mir-34a

1

NOS2A

4843

20675358

hsa-miR-34a

hsa-mir-34a

1

MDM2

4193

20089965

hsa-miR-34a

hsa-mir-34a

1

MYC

4609

19167416

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19714243

hsa-miR-34a

hsa-mir-34a

1

POU4F2

5458

14697198

hsa-miR-34a

hsa-mir-34a

1

MITF

4286

21051724

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20428827

hsa-miR-34a

hsa-mir-34a

1

CDK6

1021

19773441

hsa-miR-34a

hsa-mir-34a

1

CDK6

1021

18719384

hsa-miR-34a

hsa-mir-34a

1

PRB1

5542

17976522

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

17554199

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19584398

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

21216258

hsa-miR-34a

hsa-mir-34a

1

MDM2

4193

20581456

hsa-miR-34a

hsa-mir-34a

1

SSSCA1

10534

20018759

hsa-miR-34a

hsa-mir-34a

1

MET

4233

19029026

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

21399872

hsa-miR-34a

hsa-mir-34a

1

OCA2

4948

20388802

hsa-miR-34a

hsa-mir-34a

1

TNRC6A

27327

20976148

hsa-miR-34a

hsa-mir-34a

1

VEGFA

7422

20420713

hsa-miR-34a

hsa-mir-34a

1

WNT1

7471

19398721

hsa-miR-34a

hsa-mir-34a

1

MET

4233

20466628

hsa-miR-34a

hsa-mir-34a

1

CCNE2

9134

18834857

hsa-miR-34a

hsa-mir-34a

1

CTNNBIP1

56998

21182263

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

20439489

hsa-miR-34a

hsa-mir-34a

1

CDK6

1021

19960022

hsa-miR-34a

hsa-mir-34a

1

MYC

4609

18823940

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

18633110

hsa-miR-34a

hsa-mir-34a

1

ING2

3622

18451145

hsa-miR-34a

hsa-mir-34a

1

TIMM8A

1678

21321636

hsa-miR-34a

hsa-mir-34a

1

IFNG

3458

20857148

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

20185821

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19221490

hsa-miR-34a

hsa-mir-34a

1

HMGA2

8091

17976522

hsa-miR-34a

hsa-mir-34a

1

MDM2

4193

19461653

hsa-miR-34a

hsa-mir-34a

1

LOX

4015

21224215

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20675358

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20089965

hsa-miR-34a

hsa-mir-34a

1

MYCN

4613

19167416

hsa-miR-34a

hsa-mir-34a

1

PROM1

8842

19714243

hsa-miR-34a

hsa-mir-34a

1

PTEN

5728

14697198

hsa-miR-34a

hsa-mir-34a

1

ZNF135

7694

21047409

hsa-miR-34a

hsa-mir-34a

1

FOXO1

2308

20424141

hsa-miR-34a

hsa-mir-34a

1

MET

4233

19773441

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

18719384

hsa-miR-34a

hsa-mir-34a

1

HMGA2

8091

17554199

hsa-miR-34a

hsa-mir-34a

1

MYB

4602

19584398

hsa-miR-34a

hsa-mir-34a

1

SPI1

6688

21211043

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20581456

hsa-miR-34a

hsa-mir-34a

1

DDIT4

54541

20018759

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19029026

hsa-miR-34a

hsa-mir-34a

1

STMN1

3925

12554860

hsa-miR-34a

hsa-mir-34a

1

SLC2A1

6513

20388802

hsa-miR-34a

hsa-mir-34a

1

SCPEP1

59342

20976148

hsa-miR-34a

hsa-mir-34a

1

SEMA6A

57556

20420713

hsa-miR-34a

hsa-mir-34a

1

ST3GAL4

6484

19372595

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20466628

hsa-miR-34a

hsa-mir-34a

1

MAPK14

1432

20212154

hsa-miR-34a

hsa-mir-34a

1

FOXJ1

2302

21088493

hsa-miR-34a

hsa-mir-34a

1

AKT1

207

20433755

hsa-miR-34a

hsa-mir-34a

1

E2F1

1869

19960022

hsa-miR-34a

hsa-mir-34a

1

NOTCH1

4851

18823940

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

18505919

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

18451145

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

21321636

hsa-miR-34a

hsa-mir-34a

1

CCND1

595

20734047

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20170545

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

19221490

hsa-miR-34a

hsa-mir-34a

1

CD19

930

17934639

hsa-miR-34a

hsa-mir-34a

1

MDM4

4194

19461653

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

21224215

hsa-miR-34a

hsa-mir-34a

1

GRM3

2913

20675101

hsa-miR-34a

hsa-mir-34a

1

ATN1

1822

20086228

hsa-miR-34a

hsa-mir-34a

1

PTEN

5728

19167416

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19421141

hsa-miR-34a

hsa-mir-34a

1

BDNF

627

14697198

hsa-miR-34a

hsa-mir-34a

1

ZNF77

58492

21047409

hsa-miR-34a

hsa-mir-34a

1

PROM1

8842

20424141

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19773441

hsa-miR-34a

hsa-mir-34a

1

MDM2

4193

18711402

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

17540599

hsa-miR-34a

hsa-mir-34a

1

CDKN1A

1026

19643983

hsa-miR-34a

hsa-mir-34a

1

KLF4

9314

21211043

hsa-miR-34a

hsa-mir-34a

1

TCL1A

8115

20581456

hsa-miR-34a

hsa-mir-34a

1

HMG2L1

10042

20018759

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

18942116

hsa-miR-34a

hsa-mir-34a

1

DDX20

11218

12554860

hsa-miR-34a

hsa-mir-34a

1

PEA15

8682

20388802

hsa-miR-34a

hsa-mir-34a

1

CEBPA

1050

20889924

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20386864

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

19347736

hsa-miR-34a

hsa-mir-34a

1

FASN

2194

20213410

hsa-miR-34a

hsa-mir-34a

1

MYC

4609

20212154

hsa-miR-34a

hsa-mir-34a

1

CDC20B

166979

21088493

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

20433755

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19960022

hsa-miR-34a

hsa-mir-34a

1

HELLS

3070

18823940

hsa-miR-34a

hsa-mir-34a

1

MYCN

4613

18505919

hsa-miR-34a

hsa-mir-34a

1

MYCN

4613

18504438

hsa-miR-34a

hsa-mir-34a

1

MYC

4609

21297663

hsa-miR-34a

hsa-mir-34a

1

CDKN1A

1026

20734047

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20150330

hsa-miR-34a

hsa-mir-34a

1

MYC

4609

19211792

hsa-miR-34a

hsa-mir-34a

1

SOAT1

6646

17934639

hsa-miR-34a

hsa-mir-34a

1

MET

4233

19461653

hsa-miR-34a

hsa-mir-34a

1

VEGFA

7422

21224215

hsa-miR-34a

hsa-mir-34a

1

PHGDH

26227

20675101

hsa-miR-34a

hsa-mir-34a

1

IL1B

3553

20086228

hsa-miR-34a

hsa-mir-34a

1

ZEB1

6935

19167416

hsa-miR-34a

hsa-mir-34a

1

AKT1

207

19115258

hsa-miR-34a

hsa-mir-34a

1

CXCL12

6387

14697198

hsa-miR-34a

hsa-mir-34a

1

RUNX2

860

21042576

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

20424141

hsa-miR-34a

hsa-mir-34a

1

ZAP70

7535

19717645

hsa-miR-34a

hsa-mir-34a

1

MDM4

4194

18711402

hsa-miR-34a

hsa-mir-34a

1

BIRC3

330

17540599

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19643983

hsa-miR-34a

hsa-mir-34a

1

LEF1

51176

21211043

hsa-miR-34a

hsa-mir-34a

1

CISH

1154

20548288

hsa-miR-34a

hsa-mir-34a

1

ARIH2

10425

20018759

hsa-miR-34a

hsa-mir-34a

1

BCL6

604

18942116

hsa-miR-34a

hsa-mir-34a

1

EIF2C2

27161

12554860

hsa-miR-34a

hsa-mir-34a

1

E2F1

1869

20889924

hsa-miR-34a

hsa-mir-34a

1

NOTCH1

4851

20351093

hsa-miR-34a

hsa-mir-34a

1

MCL1

4170

19347736

hsa-miR-34a

hsa-mir-34a

1

LIN28

79727

19211792

hsa-miR-34a

hsa-mir-34a

1

HES1

3280

20213410

hsa-miR-34a

hsa-mir-34a

1

MAPKAPK2

9261

20212154

hsa-miR-34a

hsa-mir-34a

1

AKT1

207

21067862

hsa-miR-34a

hsa-mir-34a

1

NFKB1

4790

20433755

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

19960022

hsa-miR-34a

hsa-mir-34a

1

SLC11A1

6556

18823940

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

18497571

hsa-miR-34a

hsa-mir-34a

1

BBC3

27113

18941118

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

21297663

hsa-miR-34a

hsa-mir-34a

1

TIMM8A

1678

20734047

hsa-miR-34a

hsa-mir-34a

1

DDX4

54514

20150330

hsa-miR-34a

hsa-mir-34a

1

SOCS1

8651

17934639

hsa-miR-34a

hsa-mir-34a

1

MYB

4602

19461653

hsa-miR-34a

hsa-mir-34a

1

HDAC9

9734

21224215

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

20627091

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

20049626

hsa-miR-34a

hsa-mir-34a

1

ZEB2

9839

19167416

hsa-miR-34a

hsa-mir-34a

1

PIK3CA

5290

19115258

hsa-miR-34a

hsa-mir-34a

1

VAMP2

6844

14697198

hsa-miR-34a

hsa-mir-34a

1

PPARG

5468

21042576

hsa-miR-34a

hsa-mir-34a

1

ERBB4

2066

20420713

hsa-miR-34a

hsa-mir-34a

1

CDKN1A

1026

19701195

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

18711402

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

17540598

hsa-miR-34a

hsa-mir-34a

1

MYC

4609

19696787

hsa-miR-34a

hsa-mir-34a

1

CDKN1A

1026

21205967

hsa-miR-34a

hsa-mir-34a

1

RPS19

6223

20548288

hsa-miR-34a

hsa-mir-34a

1

BBC3

27113

20018759

hsa-miR-34a

hsa-mir-34a

1

E2F3

1871

18942116

hsa-miR-34a

hsa-mir-34a

1

GEMIN4

50628

12554860

hsa-miR-34a

hsa-mir-34a

1

E2F3

1871

20889924

hsa-miR-34a

hsa-mir-34a

1

CCND1

595

20309880

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19347736

hsa-miR-34a

hsa-mir-34a

1

LARP4

113251

20144220

hsa-miR-34a

hsa-mir-34a

1

MYCN

4613

19199973

hsa-miR-34a

hsa-mir-34a

1

HDAC9

9734

20213410

hsa-miR-34a

hsa-mir-34a

1

CSF1

1435

14697198

hsa-miR-34a

hsa-mir-34a

1

E2F3

1871

21067862

hsa-miR-34a

hsa-mir-34a

1

PAWR

5074

20433755

hsa-miR-34a

hsa-mir-34a

1

CDC20B

166979

19960022

hsa-miR-34a

hsa-mir-34a

1

CYP2A6

1548

18780894

hsa-miR-34a

hsa-mir-34a

1

MDC1

9656

18497571

hsa-miR-34a

hsa-mir-34a

1

BAX

581

18941118

hsa-miR-34a

hsa-mir-34a

1

TLR4

7099

21266501

hsa-miR-34a

hsa-mir-34a

1

FASN

2194

20734047

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

17894887

hsa-miR-34a

hsa-mir-34a

1

SFRS2

6427

19461653

hsa-miR-34a

hsa-mir-34a

1

MAP1LC3A

84557

21224215

hsa-miR-34a

hsa-mir-34a

1

MDM2

4193

20606648

hsa-miR-34a

hsa-mir-34a

1

E2F1

1869

20049626

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19074876

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19115258

hsa-miR-34a

hsa-mir-34a

1

UBL4A

8266

14697198

hsa-miR-34a

hsa-mir-34a

1

BAMBI

25805

21042576

hsa-miR-34a

hsa-mir-34a

1

KCNMA1

3778

20420713

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19701195

hsa-miR-34a

hsa-mir-34a

1

EPHB2

2048

18704095

hsa-miR-34a

hsa-mir-34a

1

E2F3

1871

17297439

hsa-miR-34a

hsa-mir-34a

1

NOL3

8996

19696787

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

21205967

hsa-miR-34a

hsa-mir-34a

1

COX8A

1351

20508945

hsa-miR-34a

hsa-mir-34a

1

DKK2

27123

20018759

hsa-miR-34a

hsa-mir-34a

1

NOTCH1

4851

18942116

hsa-miR-34a

hsa-mir-34a

1

RNPC3

55599

12554860

hsa-miR-34a

hsa-mir-34a

1

ACSL1

2180

21366874

hsa-miR-34a

hsa-mir-34a

1

NFYC

4802

20889907

hsa-miR-34a

hsa-mir-34a

1

MET

4233

20309880

hsa-miR-34a

hsa-mir-34a

1

SEC24D

9871

19336450

hsa-miR-34a

hsa-mir-34a

1

CNN3

1266

20144220

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19167416

hsa-miR-34a

hsa-mir-34a

1

DLL1

28514

20213410

hsa-miR-34a

hsa-mir-34a

1

EZH2

2146

14697198

hsa-miR-34a

hsa-mir-34a

1

PIK3CA

5290

21067862

hsa-miR-34a

hsa-mir-34a

1

RNASEN

29102

20433755

hsa-miR-34a

hsa-mir-34a

1

CD47

961

19952055

hsa-miR-34a

hsa-mir-34a

1

PPIG

9360

18780894

hsa-miR-34a

hsa-mir-34a

1

STK39

27347

18497571

hsa-miR-34a

hsa-mir-34a

1

MET

4233

19006648

hsa-miR-34a

hsa-mir-34a

1

MAP3K9

4293

21266077

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20734047

hsa-miR-34a

hsa-mir-34a

1

E2F1

1869

17894887

hsa-miR-34a

hsa-mir-34a

1

HMGA2

8091

19461653

hsa-miR-34a

hsa-mir-34a

1

MDM2

4193

21217645

hsa-miR-34a

hsa-mir-34a

1

MYC

4609

20606648

hsa-miR-34a

hsa-mir-34a

1

E2F3

1871

20049626

hsa-miR-34a

hsa-mir-34a

1

CDKN1A

1026

19074875

hsa-miR-34a

hsa-mir-34a

1

ACTB

60

18835850

hsa-miR-34a

hsa-mir-34a

1

NOTCH1

4851

17150773

hsa-miR-34a

hsa-mir-34a

1

CRIM1

51232

21042576

hsa-miR-34a

hsa-mir-34a

1

LOX

4015

20420713

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

19697704

hsa-miR-34a

hsa-mir-34a

1

GRM7

2917

18704095

hsa-miR-34a

hsa-mir-34a

1

PTEN

5728

16762633

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

20689156

hsa-miR-34a

hsa-mir-34a

1

ZAP70

7535

21205967

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20470934

hsa-miR-34a

hsa-mir-34a

1

TBK1

29110

20018759

hsa-miR-34a

hsa-mir-34a

1

ZEB2

9839

18942116

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19158830

hsa-miR-34a

hsa-mir-34a

1

BCR

613

21323860

hsa-miR-34a

hsa-mir-34a

1

APC

324

20883704

hsa-miR-34a

hsa-mir-34a

1

EPHB2

2048

20299489

hsa-miR-34a

hsa-mir-34a

1

WNT1

7471

19336450

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

20687223

hsa-miR-34a

hsa-mir-34a

1

EIF2C4

192670

20144220

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

19167416

hsa-miR-34a

hsa-mir-34a

1

DICER1

23405

20019750

hsa-miR-34a

hsa-mir-34a

1

G6PD

2539

14697198

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

21067862

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

20428827

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19948396

hsa-miR-34a

hsa-mir-34a

1

CDKN1A

1026

18755897

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

17996645

hsa-miR-34a

hsa-mir-34a

1

CDK4

1019

19461653

hsa-miR-34a

hsa-mir-34a

1

CD44

960

21240262

hsa-miR-34a

hsa-mir-34a

1

E2F3

1871

17894887

hsa-miR-34a

hsa-mir-34a

1

CAV1

857

19461653

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

21217645

hsa-miR-34a

hsa-mir-34a

1

VEGFA

7422

20606648

hsa-miR-34a

hsa-mir-34a

1

RB1

5925

20049626

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19074875

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

18803879

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

17656095

hsa-miR-34a

hsa-mir-34a

1

CDKN2A

1029

20978195

hsa-miR-34a

hsa-mir-34a

1

PTPN13

5783

20420713

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

19683563

hsa-miR-34a

hsa-mir-34a

1

PTPN12

5782

16762633

hsa-miR-34a

hsa-mir-34a

1

IRS1

3667

18834857

hsa-miR-34a

hsa-mir-34a

1

ANP32B

10541

21205967

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

20470934

hsa-miR-34a

hsa-mir-34a

1

MYBL1

4603

20018759

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

18834855

hsa-miR-34a

hsa-mir-34a

1

PTEN

5728

18704095

hsa-miR-34a

hsa-mir-34a

1

CDK6

1021

18406353

hsa-miR-34a

hsa-mir-34a

1

PPP1R13L

10848

21323860

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20883704

hsa-miR-34a

hsa-mir-34a

1

MAP2K1

5604

20299489

hsa-miR-34a

hsa-mir-34a

1

AXIN2

8313

19336450

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

21240262

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

20687223

hsa-miR-34a

hsa-mir-34a

1

ELK3

2004

20144220

hsa-miR-34a

hsa-mir-34a

1

PRMT5

10419

19167416

hsa-miR-34a

hsa-mir-34a

1

BCL2

596

19714243

hsa-miR-34a

hsa-mir-34a

1

DLL1

28514

14697198

hsa-miR-34a

hsa-mir-34a

1

CDK6

1021

21051724

hsa-miR-34a

hsa-mir-34a

1

E2F1

1869

20428827

hsa-miR-34a

hsa-mir-34a

1

COL11A2

1302

19921694

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

18755897

hsa-miR-34a

hsa-mir-34a

1

HBEGF

1839

17976522

hsa-miR-34a

hsa-mir-34a

1

CDK6

1021

19461653

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

17875987

hsa-miR-34a

hsa-mir-34a

1

RNMT

8731

19461653

hsa-miR-34a

hsa-mir-34a

1

GABPA

2551

21216258

hsa-miR-34a

hsa-mir-34a

1

NDRG1

10397

20606648

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

20049626

hsa-miR-34a

hsa-mir-34a

1

MCL1

4170

19074875

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

18803879

hsa-miR-34a

hsa-mir-34a

1

SYNE1

23345

18258830

hsa-miR-34a

hsa-mir-34a

1

COX8A

1351

20978195

hsa-miR-34a

hsa-mir-34a

1

SFRP1

6422

20420713

hsa-miR-34a

hsa-mir-34a

1

TP53

7157

19443717

hsa-miR-34a

hsa-mir-34a

1

ECD

11319

12812784

hsa-miR-34a

hsa-mir-34a

1

TOM1

10043

18834857

hsa-miR-34a

hsa-mir-34a

1

BBC3

27113

21205967

hsa-miR-34a

hsa-mir-34a

1

LIF

3976

20439489

hsa-miR-34a

hsa-mir-34a

1

CREBZF

58487

20018759

hsa-miR-34a

hsa-mir-34a

1

SIRT1

23411

18834855

hsa-miR-34a

hsa-mir-34a

1

CDKN1A

1026

18677110

hsa-miR-34a

hsa-mir-34a

1

CCND1

595

18406353

hsa-miR-34a

hsa-mir-34a

1

RTEL1

51750

21323860

hsa-miR-34a

hsa-mir-34a

1

SND1

27044

20883704

hsa-miR-34a

hsa-mir-34a

1

MET

4233

20190569

hsa-miR-34a

hsa-mir-34a

1

NPC1

4864

19293812

hsa-miR-342-5p

hsa-mir-342

14

ERBB2

2064

19432961

hsa-miR-342-5p

hsa-mir-342

14

CCPG1

9236

18700954

hsa-miR-342-5p

hsa-mir-342

14

ERBB2

2064

21172025

hsa-miR-342-5p

hsa-mir-342

14

BCL2

596

19284987

hsa-miR-342-5p

hsa-mir-342

14

GULP1

51454

18700954

hsa-miR-342-5p

hsa-mir-342

14

EGFR

1956

20818338

hsa-miR-342-5p

hsa-mir-342

14

IRAK2

3656

19284987

hsa-miR-342-5p

hsa-mir-342

14

IRAK2

3656

18508790

hsa-miR-342-5p

hsa-mir-342

14

KRAS

3845

20818338

hsa-miR-342-5p

hsa-mir-342

14

IRF1

3659

19151778

hsa-miR-342-5p

hsa-mir-342

14

JAK2

3717

18508790

hsa-miR-342-5p

hsa-mir-342

14

IL1B

3553

20716963

hsa-miR-342-5p

hsa-mir-342

14

IRF9

10379

19151778

hsa-miR-342-5p

hsa-mir-342

14

HMGA2

8091

18508790

hsa-miR-342-5p

hsa-mir-342

14

IRAK1

3654

20716963

hsa-miR-342-5p

hsa-mir-342

14

TRIM63

84676

19151778

hsa-miR-342-5p

hsa-mir-342

14

BCL2

596

17260024

hsa-miR-342-5p

hsa-mir-342

14

MECP2

4204

20716963

hsa-miR-342-5p

hsa-mir-342

14

CDKN1B

1027

18708351

hsa-miR-342-5p

hsa-mir-342

14

NFKB1

4790

17260024

hsa-miR-342-5p

hsa-mir-342

14

CD4

920

20448109

hsa-miR-342-5p

hsa-mir-342

14

ERBB2

2064

18708351

hsa-miR-342-5p

hsa-mir-342

14

CD4

920

19954774

hsa-miR-342-5p

hsa-mir-342

14

SSSCA1

10534

18708351

hsa-miR-342-5p

hsa-mir-342

14

IL2RA

3559

19954774

hsa-miR-342-5p

hsa-mir-342

14

TACSTD1

4072

18700954

hsa-miR-342-5p

hsa-mir-342

14

IL7R

3575

19954774

hsa-miR-342-5p

hsa-mir-342

14

MEST

4232

18700954

hsa-miR-298

hsa-mir-298

20

BACE1

23621

20375468

hsa-miR-298

hsa-mir-298

20

CYP3A4

1576

19581388

hsa-miR-298

hsa-mir-298

20

VDR

7421

19581388

hsa-miR-298

hsa-mir-298

20

BACE1

23621

18986979

hsa-miR-298

hsa-mir-298

20

CDKN1A

1026

20190813

hsa-miR-298

hsa-mir-298

20

PAK3

5063

20190813

hsa-miR-298

hsa-mir-298

20

DICER1

23405

20375468

hsa-miR-214*

hsa-mir-214

1

PTEN

5728

21228352

hsa-miR-214*

hsa-mir-214

1

MYOD1

4654

19818710

hsa-miR-214*

hsa-mir-214

1

CD28

940

20548023

hsa-miR-214*

hsa-mir-214

1

NEUROG3

50674

18023200

hsa-miR-214*

hsa-mir-214

1

AKT1

207

20400975

hsa-miR-214*

hsa-mir-214

1

CALB1

793

21363966

hsa-miR-214*

hsa-mir-214

1

VEGFA

7422

21080911

hsa-miR-214*

hsa-mir-214

1

NOS3

4846

19733659

hsa-miR-214*

hsa-mir-214

1

PTEN

5728

20548023

hsa-miR-214*

hsa-mir-214

1

NBN

4683

18230126

hsa-miR-214*

hsa-mir-214

1

CD44

960

20400975

hsa-miR-214*

hsa-mir-214

1

EZH2

2146

21363966

hsa-miR-214*

hsa-mir-214

1

ZNRD1

30834

21080911

hsa-miR-214*

hsa-mir-214

1

APC

324

19701500

hsa-miR-214*

hsa-mir-214

1

CDKN1A

1026

20534588

hsa-miR-214*

hsa-mir-214

1

IKBKB

3551

20400975

hsa-miR-214*

hsa-mir-214

1

PRNP

5621

21363966

hsa-miR-214*

hsa-mir-214

1

MYC

4609

20716115

hsa-miR-214*

hsa-mir-214

1

CTNNB1

1499

19701500

hsa-miR-214*

hsa-mir-214

1

NRAS

4893

20534588

hsa-miR-214*

hsa-mir-214

1

PTEN

5728

20400975

hsa-miR-214*

hsa-mir-214

1

ENAM

10117

21363966

hsa-miR-214*

hsa-mir-214

1

PAK1

5058

20716115

hsa-miR-214*

hsa-mir-214

1

DCT

1638

19546168

hsa-miR-214*

hsa-mir-214

1

ATP2A2

488

20498046

hsa-miR-214*

hsa-mir-214

1

TWIST1

7291

20400975

hsa-miR-214*

hsa-mir-214

1

MOCOS

55034

21358347

hsa-miR-214*

hsa-mir-214

1

PTEN

5728

20716115

hsa-miR-214*

hsa-mir-214

1

MYC

4609

19435428

hsa-miR-214*

hsa-mir-214

1

CCND2

894

20498046

hsa-miR-214*

hsa-mir-214

1

RAB22A

57403

20302635

hsa-miR-214*

hsa-mir-214

1

COX8A

1351

21345725

hsa-miR-214*

hsa-mir-214

1

ZEB1

6935

20716115

hsa-miR-214*

hsa-mir-214

1

TGFBR2

7048

19435428

hsa-miR-214*

hsa-mir-214

1

JUN

3725

20498046

hsa-miR-214*

hsa-mir-214

1

TOP2B

7155

20219416

hsa-miR-214*

hsa-mir-214

1

SOX9

6662

21288128

hsa-miR-214*

hsa-mir-214

1

DICER1

23405

20716115

hsa-miR-214*

hsa-mir-214

1

TACSTD1

4072

18589210

hsa-miR-214*

hsa-mir-214

1

TCF3

6929

20498046

hsa-miR-214*

hsa-mir-214

1

MAPK8

5599

19859982

hsa-miR-214*

hsa-mir-214

1

EGFL7

51162

21288128

hsa-miR-214*

hsa-mir-214

1

EIF2C1

26523

20716115

hsa-miR-214*

hsa-mir-214

1

AKT1

207

18199536

hsa-miR-214*

hsa-mir-214

1

KLF4

9314

20498046

hsa-miR-214*

hsa-mir-214

1

MAP2K3

5606

19859982

hsa-miR-214*

hsa-mir-214

1

ROBO2

6092

21276775

hsa-miR-214*

hsa-mir-214

1

EIF2C2

27161

20716115

hsa-miR-214*

hsa-mir-214

1

BIRC3

330

18199536

hsa-miR-214*

hsa-mir-214

1

SH2B2

10603

20498046

hsa-miR-214*

hsa-mir-214

1

EZH2

2146

19818710

hsa-miR-214*

hsa-mir-214

1

SRGAP2

23380

21276775

hsa-miR-214*

hsa-mir-214

1

RAG2

5897

20651252

hsa-miR-214*

hsa-mir-214

1

PTEN

5728

18199536

hsa-miR-214*

hsa-mir-214

1

STMN2

11075

20498046

hsa-miR-214*

hsa-mir-214

1

AMELX

265

21363966

Table 3

miRNAs validated targets, hierarchical order

Gene name

Hits

Gene name

Hits

Gene name

Hits

Gene name

Hits

Gene name

Hits

Gene name

Hits

Gene name

Hits

DICER1

5

LIN28

2

CD46

1

G6PD

1

MAP2K3

1

POU2F2

1

SPI1

1

CDKN1A

4

MAPK8

2

CD47

1

GABPA

1

MAP3K12

1

POU4F2

1

SRGAP2

1

NFKB1

4

MECP2

2

CDC14A

1

GHRHR

1

MAP3K9

1

PPARG

1

ST3GAL4

1

TP53

4

MITF

2

CDC20B

1

GRB2

1

MAPK14

1

PPIG

1

STAT3

1

VEGFA

4

MYCN

2

CDC25C

1

GRIA1

1

MAPK3

1

PPP1R13L

1

STK39

1

APC

3

PAK3

2

CDC42

1

GRIN2A

1

MAPKAPK2

1

PRB1

1

STMN2

1

BCL2

3

PROM1

2

CDH1

1

GRIN2B

1

MCL1

1

PRDM1

1

SYNE1

1

CD44

3

PTEN

2

CDK4

1

GRM3

1

MDC1

1

PRKAR1A

1

TARBP2

1

CDC25A

3

SCPEP1

2

CDKN1B

1

GRM7

1

MDM2

1

PRMT5

1

TBK1

1

CDK6

3

SIRT1

2

CEBPB

1

GSX2

1

MDM4

1

PRNP

1

TCF21

1

EIF2C1

3

SOAT1

2

CHEK1

1

GULP1

1

MEIS2

1

PTPN12

1

TCF3

1

EIF2C2

3

SSSCA1

2

CHRD

1

HBEGF

1

MEST

1

PTPN13

1

TCL1A

1

HDAC9

3

STMN1

2

CISH

1

HDAC1

1

MET

1

PXMP2

1

TGFBR2

1

IL1B

3

TACSTD1

2

CKAP4

1

HDAC2

1

MGST1

1

RAB22A

1

TGIF2

1

KRAS

3

TLR4

2

CNN3

1

HELLS

1

MMP13

1

RAB34

1

TIMM8A

1

MYC

3

TP73

2

COL11A2

1

HES1

1

MOCOS

1

RAG2

1

TLR2

1

RNASEN

3

WNT1

2

COL2A1

1

HGF

1

MPI

1

RASSF1

1

TNRC6A

1

AKT1

2

ZEB1

2

COL9A1

1

HLCS

1

MYB

1

RB1

1

TOM1

1

ATN1

2

ACSL1

1

COMP

1

HMG2L1

1

MYBL1

1

RBBP6

1

TOP2B

1

BACE1

2

ACTB

1

CREBZF

1

HMOX1

1

MYD88

1

RCOR1

1

TRIM63

1

BCL6

2

AMELX

1

CRIM1

1

HNF4A

1

MYOD1

1

RELB

1

TRPM3

1

BDNF

2

ANLN

1

CSF1

1

HOXA5

1

NBN

1

REST

1

TWIST1

1

BIRC3

2

ANP32B

1

CTNNB1

1

HRB

1

NDRG1

1

RGS3

1

UBL4A

1

CCND1

2

ARCN1

1

CTNNBIP1

1

HUWE1

1

NDUFA2

1

RNMT

1

VAMP2

1

CCNE2

2

ARIH2

1

CXCL12

1

IGF1

1

NEUROD1

1

RNPC3

1

VDR

1

CDKN2A

2

ATF6

1

CYP2A6

1

IGFALS

1

NEUROG3

1

ROBO2

1

WEE1

1

CDKN2D

2

ATP2A2

1

CYP3A4

1

IKBKB

1

NF2

1

ROS1

1

WISP2

1

CEBPA

2

ATP6V1B2

1

DCT

1

IL2RA

1

NFE2L2

1

RPE

1

XPO5

1

COX8A

2

AXIN2

1

DDIT3

1

IL7R

1

NFYC

1

RPS19

1

YY1

1

CREB1

2

BAMBI

1

DDIT4

1

ING2

1

NOG

1

RTEL1

1

ZAP70

1

DDX20

2

BAX

1

DDX4

1

IRAK1

1

NOL3

1

RUNX1

1

ZEB2

1

DGCR8

2

BBC3

1

DKK2

1

IRAK2

1

NOS2A

1

RUNX2

1

ZNF135

1

E2F1

2

BCR

1

DLL1

1

IRF1

1

NOS3

1

RUNX3

1

ZNF77

1

E2F3

2

BNIP3L

1

DNMT1

1

IRF9

1

NOTCH1

1

SEC24D

1

ZNF828

1

E2F5

2

BRAP

1

ECD

1

IRS1

1

NPAT

1

SEMA6A

1

ZNRD1

1

ELSPBP1

2

BRCA1

1

EDG6

1

JAG1

1

NPC1

1

SERPINE1

1

  

EPHB2

2

C1orf183

1

EGFL7

1

JARID1B

1

NR1H4

1

SFRP1

1

  

ERBB2

2

C1orf61

1

EGFR

1

KCNMA1

1

NR2E1

1

SFRS2

1

  

EZH2

2

C9orf127

1

EIF2C4

1

KIF23

1

NRAS

1

SH2B2

1

  

FASN

2

CALB1

1

ELAVL1

1

KIT

1

NTRK3

1

SLC11A1

1

  

FOXO1

2

CAV1

1

ELAVL2

1

LAMC2

1

OCA2

1

SLC12A1

1

  

FOXP1

2

CBX7

1

ELK3

1

LARP4

1

PAK1

1

SLC22A3

1

  

FRAP1

2

CCND2

1

ENAM

1

LARP6

1

PAWR

1

SLC27A4

1

  

GEMIN4

2

CCND3

1

ERBB4

1

LEF1

1

PAX6

1

SLC2A1

1

  

HMGA2

2

CCNE1

1

ETS1

1

LIF

1

PDGFA

1

SLC7A5

1

  

IFNG

2

CCNF

1

FGF8

1

LMX1A

1

PEA15

1

SMARCA5

1

  

IL6

2

CCPG1

1

FMR1

1

LOX

1

PHGDH

1

SND1

1

  

JAK2

2

CD19

1

FOXG1

1

LRPAP1

1

PIK3CA

1

SOCS1

1

  

JUN

2

CD28

1

FOXJ1

1

MAP1LC3A

1

PIWIL1

1

SOX2

1

  

KLF4

2

CD4

1

FZR1

1

MAP2K1

1

PMP22

1

SOX9

1

  
Table 4

Putative LMNA ceRNAs GO functions

GO Annotation

False Discovery Rate

post-transcriptional gene silencing by RNA

8.71E-4

gene silencing by miRNA

8.71E-4

post-transcriptional gene silencing

8.71E-4

cellular response to abiotic stimulus

1.11E-3

response to abiotic stimulus

1.11E-3

gene silencing by RNA

1.11E-3

production of miRNAs involved in gene silencing by miRNA

2.64E-3

cell ageing

2.64E-3

cyclin-dependent protein kinase holoenzyme complex

2.64E-3

dsRNA fragmentation

2.8E-3

production of small RNA involved in gene silencing by RNA

2.8E-3

gene silencing

3.84E-3

regulation of homeostatic process

3.84E-3

ageing

3.84E-3

regulation of cyclin-dependent protein kinase activity

3.84E-3

regulation of cell motility

4.01E-3

cellular response to dsRNA

4.29E-3

regulation of protein serine/threonine kinase activity

4.61E-3

regulation of cellular component movement

4.61E-3

regulation of locomotion

4.61E-3

response to dsRNA

4.94E-3

positive regulation of protein phosphorylation

7.51E-3

response to radiation

8.64E-3

cellular response to hypoxia

8.97E-3

cellular senescence

9.78E-3

positive regulation of phosphorylation

9.95E-3

positive regulation of phosphorus metabolic process

1.02E-2

response to drug

1.02E-2

positive regulation of phosphate metabolic process

1.02E-2

cellular response to oxygen levels

1.02E-2

RNA helicase activity

1.12E-2

vascular endothelial growth factor receptor signaling pathway

1.74E-2

Ras guanyl-nucleotide exchange factor activity

1.74E-2

positive regulation of endothelial cell migration

1.8E-2

regulation of gene expression, epigenetic

1.8E-2

cellular response to radiation

2.08E-2

regulation of cell migration

2.15E-2

cellular response to vascular endothelial growth factor stimulus

2.15E-2

nuclear periphery

3.77E-2

positive regulation of angiogenesis

4.47E-2

cellular response to external stimulus

4.49E-2

small GTPase mediated signal transduction

4.49E-2

positive regulation of cell migration

4.49E-2

regulation of endothelial cell migration

4.59E-2

positive regulation of cell motility

4.6E-2

positive regulation of cell adhesion

4.94E-2

positive regulation of locomotion

5.07E-2

positive regulation of cellular component movement

5.1E-2

cellular response to drug

5.53E-2

endoribonuclease activity, producing 5'-phosphomonoesters

5.53E-2

positive regulation of vascular endothelial growth factor receptor signaling pathway

5.53E-2

cyclin-dependent protein kinase activity

5.53E-2

positive regulation of protein modification process

6.09E-2

helicase activity

7.11E-2

G1/S transition of mitotic cell cycle

7.19E-2

regulation of chromosome organization

7.19E-2

regulation of cell aging

7.38E-2

positive regulation of peptidyl-tyrosine phosphorylation

8.34E-2

regulation of vascular endothelial growth factor receptor signaling pathway

8.42E-2

ncRNA metabolic process

9.24E-2

endonuclease activity, active with either ribo- or deoxyribonucleic acids and producing 5'- phosphomonoesters

9.24E-2

regulation of cellular response to growth factor stimulus

9.24E-2

angiogenesis

9.24E-2

endothelial cell migration

9.59E-2

response to hypoxia

9.59E-2

response to oxygen levels

9.92E-2

cellular response to UV

9.92E-2

Cell migration involved in sprouting angiogenesis

9.92E-2

Results and discussion

A ceRNA analysis might reveal genes that are co-regulated post-transcriptionally and that can be functionally correlated [13]. The 3’UTR of the longest transcript of the LMNA human gene was selected for the analysis because the vast majority of miRNAs recognize and regulate the efficiency of transcription by binding to this portion of messenger RNAs [13]. Moreover, the 3’UTR of the longest transcript is shared between Lamin-A and progerin splicing form, and it is different form the shorter 3’UTR of the Lamin-C transcript, not used in this study. The miRWalk database and tools [14] were used to perform the analysis. The database reported no validated miRNAs that bind to the 3’UTR of the main transcript of the LMNA gene. By contrast, in this study, predicted miRNAs able to bind to the 3’UTR of the main transcript of the LMNA gene were used. The predicted miRNAs are shown in Table 1.

Although the database does not report any validated miRNAs, it is to be noted that miR-9, one of the predicted miRNAs isolated, has recently been validated [17].

Amongst the isolated miRNAs worth noting is miR-214, clearly involved in cancer and stemness [18, 19]; miR-9, involved in neurogenesis [20] and, very interestingly, protective in neural cells of HGPS patients against the effects of progeria [21]; miR-298, involved in the regulation of beta-amyloid precursor protein converting enzyme messenger RNA translation, and thus in Alzheimer’s disease [22]; the tumour suppressor miR-34a [23]; and miR-449a involved in differentiation [24] and pRB mediated cell cycle arrest [25].

The correlation of the expression levels of LMNA and each miRNA was analysed using the mimiRNA software [15], which allows one to compare the expression profiles reported in different human tissues and cell lines. The data are reported in Table 1. One should expect a negative correlation between a miRNA and its regulated genes. Only 9 of the 11 miRNAs isolated could be analysed using the mimiRNA software; and amongst them 6 out of 9 showed a negative correlation, as expected, with the exception of miR-214, miR-24a and miR-532-3p.

The miRNAs in Table 1 were used as baits to find any human gene whose 3’ UTRs are recognized by them as literature validated targets, again using the miRWalk database and tools [14]. 670 couples of bait miRNA-gene were recovered. They are reported in Table 2.

Following the ceRNA hypothesis, the more miRNA were shared between the transcripts 3’UTRs, the stronger their interaction could be. The data reported in Table were organized on the basis of the quantity of miRNA reported in Table 1 able to hit the transcripts from each gene. Multiple hits from the same miRNA on the same gene were weighted as unique. Genes were then organized from the most hit to the less hit.

The results shown in Table 3 show only one gene transcript hit 5 times (DICER1); 4 gene transcripts hit 4 times (CDKN1A, NFKB1, TP53, VEGFA); 12 gene transcripts hit 3 times (APC, BCL2, CD44, CDC25A, CDK6, EIF2C1, EIF2C2, HDAC9, IL1B, KRAS, MYC, RNASEN); 51 gene transcripts hit 2 times; and 267 gene transcripts hit only once.

Arbitrarily, further analyses were performed focusing on genes whose transcripts were hit from 3 to 5 times, because they more likely constitute ceRNAs for the LMNA transcripts. This choice was made because the higher the number of shared miRNAs, the higher the possibility that the discovered genes could act as ceRNAs. Using genes that are hit by few miRNAs could raise the risk of picking up false positives. Unfortunately, no standardization can be used on the basis of previously published data. The cut-off point was chosen taking into account ceRNAs recognized by more than 50% of miRNAs of the most hit genes: specifically genes hit by more than 2.5 miRNAs, that is 3 to 5 miRNAs, as stated. Of course this arbitrary decision could have affected the subsequent analyses, increasing the risk of false negatives, but a highly stringent strategy was preferred, taking the number of total putative ceRNAs from 422 to 17. In the literature the analysis of these 17 genes strikingly highlights a possible relationship between LMNA gene functions and RNA interference machinery: DICER1, EIF2C1, EIF2C2 and RNASEN code respectively for Dicer, Argonaute1, Argonaute2 and Drosha, the key effectors of the RNA interference machinery [26]. Interestingly, there are no data reporting a relationship between Lamin-A and RNA interference machinery. Another network involved in LMNA functions is p53 and the control of cell cycle: TP53 coding for p53 itself, while CDKN1A, CDC25A and CDK6 code respectively for p21, the phosphatase CDC25A and the cyclin-dependent protein kinase 6, differently expressed during the cell cycle and involved in bypassing the G1/S checkpoint. p53 directly regulates p21 [27] and CDC25A [28] which indirectly regulates the cyclin-dependent protein kinase 6 [29]. Notably, the expression of TP53, APC, BCL2, KRAS and MYC is very often altered in several types of human cancer [3034]. Interestingly, clear involvement of LMNA mutations in the control of cell cycle and in cancer has been reported [35]. NFKB1, IL1B and VEGFA products are involved in inflammation and cancer-related inflammation and angiogenesis [3638]. It is worth noting that coronary artery atherosclerosis typically leads to the death of HGPS patients [39] and that LMNA mutations have been linked to inflammatory myopathy [40]. Notably, it has been suggested that the splicing factor SRSF1 may have a role in driving alternative splicing forms of both LMNA and VEGFA during the senescence of endothelial cells [41].

HDAC9 codes for a histone deacetylase, a class of the epigenetic covalent modifiers, involved in the risk of ischemic stroke [42]. It has been reported that Lamin-A/C deficiency causes chromosome condensation that can be reversed by histone acetylase inhibitors [43].

CD44 codes for a surface marker of hematopoietic stem and progenitor cells and is also involved in cancer [44].

With the aim of analysing the 17 putative ceRNAs isolated, the GeneMANIA [16] tool was used. It helps to predict the functions of a set of genes and to predict in which Gene Ontology (GO) functions they might be involved. The results are reported in Table 4 from the most statistically significant to the less, up to a False Discovery Rate (FDR) < 0.1. Interestingly, posttranscriptional gene silencing by RNA, ageing, cellular senescence, G1/S transition of mitotic cell cycle and angiogenesis are all statistically significant, amongst many other GO functions.

It is to be noted that in a previous study [2] the authors used the predicted miRNAs that hit the 3’UTR of the longest transcript of the LMNA gene to find any human gene whose 3’ UTRs are recognized by them as predicted targets, not literature validated ones as in the present study, again using the miRWalk database and tools [14]. Moreover, in that study the GeneMANIA [16] tool was also used together with the Osprey visualization tool [45] of the BioGRID database [46]. The result of that study highlighted a central role of RB1 and HTATIP genes, possible involvement in prostate cancer, and a possible role of LMNA in epigenetic modification, especially acetylation events, and ATP dependent chromatin remodelling via the chromatin remodelling complexes PBAF and SWI/SNF. Taken together, these studies suggest a possible role of LMNA gene products in the control of cell cycle and tumorigenesis, chromatin remodelling, epigenetic modifications, especially acetylation via HTATIP/HDAC9, and a close link with the RNA interference machinery.

Conclusion

In HGPS there is accumulation in the nuclear membrane of the Lamin-A rare splicing form called progerin. How the accumulation of progerin leads to progeria is still under debate. The aim of this article was to investigate the network of interactions of LMNA gene to find candidate genes and gene ontology functions involved in Lamin-A functions and in turn possibly perturbed in progeria. To search for possible partners of the LMNA gene involved in HGPS and normal ageing, bioinformatics analyses of the network of interactions of the Lamin-A/progerin were performed looking for LMNA ceRNAs using Lamin-A/progerin 3’UTR as a bait. The analysis might be quite useful because it allows one to isolate possible interactors for the gene being examined and to discover novel functions in which it might be involved.

LMNA is mutated in several human diseases of genetic origin with very variable phenotypes, suggesting a multiple role of LMNA gene products in cell homeostasis and functions [47, 48]. There have been reported laminopathies due to LMNA mutations such as Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome, which is the main focus of this study. This study might help to understand why different mutations of a single gene can induce many different phenotypes in affected patients. The wide range of functions possibly involved in the LMNA network of interactions can give a plausible explanation of the many phenotypes due to LMNA mutations in humans.

The possible involvement of LMNA in the network of regulation of key cellular functions such as control of the cell cycle, epigenetics and chromatin remodelling, and RNA interference highlights a central role of Lamins in the nuclear functions. Further studies are required to better understand the relationship between LMNA products and the cellular components isolated, but a better understanding of the LMNA network might improve the quality of life of many patients affected by laminopathies. It might also enhance our comprehension of how the structural components and the functional components of the eukaryote nuclei interact.

Authors’ information

WA is a PostDoc at the Section of Endocrinology, Diabetology & Metabolism, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo, Italy. GP is a researcher at the Section of Endocrinology, Diabetology & Metabolism, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo, Italy. CG is a professor of endocrinology at the Section of Endocrinology, Diabetology & Metabolism, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo, Italy.

Abbreviations

ceRNA: 

Competing endogenous RNA

FDR: 

False Discovery Rate

GO: 

Gene Ontology

HGPS: 

Hutchinson-Gilford Progeria Syndrome

miRNA: 

Micro RNA

miR: 

Micro RNA

mRNA: 

Messenger RNA

3’UTR: 

3’ UnTranslated Region.

Declarations

Ackowledgements

Our thanks go to Dr. S.I. Genovese and D. Gailor for the help and advice given and to Giordano Bruno, Nikola Tesla and Barbara McClintock for their inspiring vision.

Authors’ Affiliations

(1)
Section of Endocrinology, Diabetology & Metabolism, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S.), University of Palermo

References

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