Open Access

The Binding Sites of miR-619-5p in the mRNAs of Human and Orthologous Genes

  • Shara Atambayeva1Email author,
  • Raigul Niyazova1,
  • Anatoliy Ivashchenko1,
  • Anna Pyrkova1,
  • Ilya Pinsky1,
  • Aigul Akimniyazova1 and
  • Siegfried Labeit2
BMC Genomics201718:428

https://doi.org/10.1186/s12864-017-3811-6

Received: 19 March 2017

Accepted: 22 May 2017

Published: 1 June 2017

Abstract

Background

Normally, one miRNA interacts with the mRNA of one gene. However, there are miRNAs that can bind to many mRNAs, and one mRNA can be the target of many miRNAs. This significantly complicates the study of the properties of miRNAs and their diagnostic and medical applications.

Results

The search of 2,750 human microRNAs (miRNAs) binding sites in 12,175 mRNAs of human genes using the MirTarget program has been completed. For the binding sites of the miR-619-5p the hybridization free energy of the bonds was equal to 100% of the maximum potential free energy. The mRNAs of 201 human genes have complete complementary binding sites of miR-619-5p in the 3’UTR (214 sites), CDS (3 sites), and 5’UTR (4 sites). The mRNAs of CATAD1, ICA1L, GK5, POLH, and PRR11 genes have six miR-619-5p binding sites, and the mRNAs of OPA3 and CYP20A1 genes have eight and ten binding sites, respectively. All of these miR-619-5p binding sites are located in the 3’UTRs. The miR-619-5p binding site in the 5’UTR of mRNA of human USP29 gene is found in the mRNAs of orthologous genes of primates. Binding sites of miR-619-5p in the coding regions of mRNAs of C8H8orf44, C8orf44, and ISY1 genes encode the WLMPVIP oligopeptide, which is present in the orthologous proteins. Binding sites of miR-619-5p in the mRNAs of transcription factor genes ZNF429 and ZNF429 encode the AHACNP oligopeptide in another reading frame. Binding sites of miR-619-5p in the 3’UTRs of all human target genes are also present in the 3’UTRs of orthologous genes of mammals. The completely complementary binding sites for miR-619-5p are conservative in the orthologous mammalian genes.

Conclusions

The majority of miR-619-5p binding sites are located in the 3’UTRs but some genes have miRNA binding sites in the 5’UTRs of mRNAs. Several genes have binding sites for miRNAs in the CDSs that are read in different open reading frames. Identical nucleotide sequences of binding sites encode different amino acids in different proteins. The binding sites of miR-619-5p in 3’UTRs, 5’UTRs and CDSs are conservative in the orthologous mammalian genes.

Keywords

miR-619-5p miRNA mRNA Gene Human Orthologous genes

Background

miRNAs participate in the regulation of the expression of protein-coding genes at the post-transcriptional stage [1]. miRNAs, as a part of the RNA-induced silencing complex, bind to mRNAs and interfere with translation or promote mRNA destruction [2]. In the last two decades, properties of miRNAs and their influences on the expression of the genes involved in all key cellular processes have been established. The actions of miRNAs on the cell cycle [3], apoptosis [4], differentiation [5], and growth and development of plants [6] and animals [7] have been shown. Connections between miRNA expression and the development of various diseases have been established. miRNA concentrations change in cancer [8] and cardiovascular diseases [9]. Metabolic perturbations change miRNA concentrations in cells [10]. The aforementioned roles do not encompass all of the biological processes in which miRNAs participate, which further proves the importance of their biological functions. Despite the significant success in the study of miRNA properties, there are obstacles in identifying the target genes of miRNAs. Normally, one miRNA interacts with the mRNA of one gene. However, there are miRNAs that can bind to many mRNAs, and one mRNA can be the target of many miRNAs, which significantly complicates the study of the properties of miRNAs and their diagnostic and medical applications. There are more than 2,500 miRNAs in the human genome, and they are believed to act on 60% or more genes. Therefore, it is difficult to draw specific conclusions about the participation of miRNAs in specific biological processes, and until then the connections between the majority of miRNAs and their target genes will remain unknown. Recently, a set of unique miRNAs (umiRNA) were identified that have hundreds of target genes and bind to mRNAs with high affinity [1114]. The binding sites of these umiRNAs are located in the 3’UTRs, CDSs, and 5’UTRs of mRNAs. Among these umiRNAs, miR-619-5p interacts with the largest number of target genes that have the greatest number of binding sites with complete complementarity of miR-619-5p and mRNAs. It is necessary to identify many miRNA binding sites in the mRNAs of these genes for the control of gene expression. Furthermore, it is important to control the expression of the corresponding gene complexes that are functionally associated with miRNAs. Therefore, we have studied a unique miR-619-5p that binds to the mRNAs of several hundred human and orthologous genes.

Methods

The nucleotide sequences of mRNAs of human genes (Homo sapience – Hsa) and orthologous genes (Bos mutus - The wild yak (Bmu), Callithrix jacchus – The common marmoset (Cja), Camelus dromedarius – Arabian camel (Cdr), Camelus ferus – The wild Bactrian camel (Cfe), Chlorocebus sabaeus – The green monkey (Csa), Colobus angolensis palliatus – The Angola colobus (Can), Equus caballus - The horse (Eca), Gorilla gorilla - The western gorilla (Ggo), Macaca fascicularis – The crab-eating macaque (Mfa), Macaca mulatta – The rhesus macaque (Mmu), Macaca nemestrina - Pig-tailed macaque (Mne), Mandrillus leucophaeus – The drill (Mle), Nomascus leucogenys - The northern white-cheeked gibbon (Nle), Ovis aries – The sheep (Oar), Pan paniscus - Bonobos (Ppa), Pan troglodytes – The common chimpanzee (Ptr), Papio anubis – The olive baboon (Pan), Pongo abelii - The Sumatran orangutan (Pab), Rhinopithecus roxellana – The golden snub-nosed monkey (Rro)) were downloaded from NCBI GenBank (http://www.ncbi.nlm.nih.gov) [15] in FASTA format using Lextractor002 script [11]. Nucleotide sequences of human mature miR-619-5p (GCUGGGAUUACAGGCAUGAGCC) were downloaded from the miRBase database (http://mirbase.org) [16]. The miR-619-5p binding sites in the 5’-untranslated regions (5’UTRs), the coding domain sequences (CDSs) and the 3’-untranslated regions (3’UTRs) of several genes were predicted using the MirTarget program [12]. This program defines the features of binding: a) the localization of miRNA binding sites in the 5’UTRs, the CDSs and the 3’UTRs of the mRNAs; b) the free energy of hybridization (∆G, kJ/mole). The ratio ΔG/ΔGm (%) was determined for each site (ΔGm equals the free energy of miRNA binding with its perfect complementary nucleotide sequence).

Results

The search of 2,750 human microRNAs (miRNAs) binding sites in 12,175 mRNAs of human genes using the MirTarget program has been completed. The mRNAs have different miRNA binding site origins, lengths, quantities, and properties. The list of miR-619-5p target genes and the positions of binding sites are outlined in Table 1. miR-619-5p is 22 nucleotides in length and is coded by an intron of the slingshot protein phosphatase 1 (SSH1) gene, which is located on chromosome 12 [17, 18]. mRNAs of 201 genes have complete complementary binding sites for miR-619-5p (ΔG/ΔGm = 100%). Therefore, the energy of interaction of miR-619-5p with mRNA of all the genes listed in the table is the same and equal to ΔG = −121 kJ/mole.
Table 1

Positions of miR-619-5p binding sites and disease or function of target genes

Gene

Site, nt

Disease or function

PMID

Gene

Site, nt

Disease or function

PMID

ACSL6

4639

prostate cancer

19064571

MRPS25

1609

uncharacterized

26302410

ADAL

2041

proliferation

23645737

MSH3

4139

carcinogenesis

24934723

ADAM17

3466

breast cancer

22967992

NANOS1

3219

retinoblastoma

25100735

AGMAT

2207

renal carcinoma

14648699

NCMAP

2259

uncharacterized

 

AK1

1449

hypertension

23863634

NDUFAF7

1697

leukemia

24292274

AKT2

4571

neuroblastoma

23468863

NDUFC2

1646

colon cancer

25804238

ALDH3A2

2617

detoxification

9829906

NLN

4215

Parkinson’s D.

25378390

ANKRD16

2165

breast cancer

20453838

NRIP2

2075

atopic asthma

17075290

AP5B1

4316

differentiation

15146197

NSL1

3063

kinetochore-protein

16585270

ARGFX

2642

development

20565723

NXPE3

7447

hepatocarcinoma

26883180

ARHGEF39

1307

tumorogenesis

22327280

OPTN

2332

glaucoma

26302410

ARL11

1033

tumorogenesis

18337727

PAG1

8156

prostatic cancer

21092590

ATCAY

2991

schizophrenia

19165527

PAQR5

4439

ovarian cancer

21761364

ATP1A2

4410

tumorogenesis

23474907

PARK2

3729

Parkinson’s D.

26860075

BCL2L15

2650

apoptosis

16690252

PBLD

2077

hepatocarcinoma

26594798

BPNT1

1128

ovarian cancer

20628624

PCGF5

5089

Alzheimer’s D.

16385451

C15orf40

523

uncharacterized

 

PCSK5

8613

tumorogenesis

21094132

C17orf75

2895

uncharacterized

 

PDAP1

1926

proliferation

23555679

C17orf75

3672

PDCD4

3221

tumorogenesis

26871813

C21orf58

2668

uncharacterized

11707072

PEX2

3056

cerebellar ataxia

21392394

C4orf19

2068

uncharacterized

 

PGPEP1

1476

liver cirrhosis

25687677

C6orf170

4113

uncharacterized

20159594

PIK3R2

3345

tumorogenesis

26677064

C8orf44

336**

uncharacterized

 

PNPLA1

1991

childhood obesity

19390624

C8orf44

1626

PODNL1

1876

uncharacterized

12477932

C9orf85

871

uncharacterized

 

POFUT1

4679

hepatocarcinoma

27003260

CACNB2

4301

hypertension

25966706

POLH

5550

ovarian cancer

25831546

CACNG8

3218

cardiomyopathy

26710323

PPM1K

2192

diabetes mellitus

23446828

CACNG8

5006

PPP1R12B

5156

childhood asthma

23640410

CACNG8

7535

PRRG4

998

Parkinson’s D

19772629

CALHM1

2896

Alzheimer’s D.

26944452

PSMB2

2925

proteolysis

21660142

CCBE1

3321

ovarian cancer

19935792

PTCD3

4116

osteosarcoma

19427859

CCDC114

261*

dyskinesia

23506398

PTK6

2233

tumorogenesis

27311570

CD109

6841

bladder cancer

20946523

QRFPR

1949

metabolic S.

16648250

CD36

4042

atherosclerosis

16515687

RAB11FIP1

4928

cell transport

26790954

CD68

1398

carcinomas

21113139

RAB3IP

3975

tumorogenesis

12007189

CDAN1

4296

erythropoiesis

19336738

7022

CDHR3

4878

asthma

25848009

RAB7L1

1693

Parkinson’s D.

26914237

CEP68

4394

cervical cancer

17570516

RBBP9

1818

tumorogenesis

21933118

CHST5

2946

colon carcinoma

12107080

RGS3

205*

cardiovascular D.

24375609

CHST6

2979

dystrophy

20539220

RPS6KA6

7136

tumorogenesis

26732474

CHST6

3876

SCN11A

5871

neurophaty

25791876

CIAO1

2416

tumorogenesis

9556563

SEPT11

4033

hepatocarcinoma

20419844

CIAO1

3814

SEPT14

1575

Parkinson’s D

27115672

CLEC19A

1747

lectin

12975309

SGTB

3142

lymphopoesis

2158125

CLTC

7006

pancreatic cancer

23228632

SH3GLB1

4856

prostate cancer

27748942

CORO2A

2227

colon cancer

23490283

SLC15A2

4333

hepatocarcinoma

25965825

COX18

1264

tumorogenesis

20819778

SLC17A5

2389

cardiovascular D

27872510

CPM

2698

renal carcinoma

23172796

SLC26A2

5066

colorectal cancer

23840040

CPM

4996

SLC26A4

4210

hearing loss

27729126

CPT2

2557

sudden death

21641254

SLC28A2

2196

chronic hepatitis C

23195617

CYB5RL

3426

transcription

16344560

SLC7A11

6304

tumorogenesis

26729415

CYP20A1

2539

tumorogenesis

15191668

SLC7A14

8487

breast cancer

20379614

CYP20A1

4709

SNX22

902

liver-disease

21988832

CYP27C1

3823

self-rated health

20707712

SOWAHC

3417

retrotransposon

22234889

CYP2W1

2176

colorectal cancer

22993331

SPATA13

5020

colorectal cancer

17599059

DAP3

1842

breast cancer

22287761

SPATA5

5648

microcephaly

26299366

DCAF10

3305

lung cancer

28336923

SPATS2

3332

breast cancer

20379614

DCAF10

4559

SPN

5287

tumorogenesis

25551301

DCLRE1C

2966

Omenn syndrome

25981738

STAC2

2241

inherited ataxias

16713569

DDOST

1782

hyperglycemia

22305527

SYNJ2BP

1298

breast cancer

19349195

DHODH

1709

melanoma

21430780

SYNJ2BP

4175

DHRS9

1281*

tumorogenesis

26254099

TCEB1

1964

tumorogenesis

23083832

DNAL1

4925

dyskinesia

15845866

TIGD6

3439

uncharacterized

 

DSCR6

1706

Down syndrome

10814524

TMEM156

1593

uncharacterized

 

ERBB3

5104

tumorogenesis

26689995

TMEM19

3510

uncharacterized

 

FADS6

1777

liver disease

21988832,

TMEM213

875

uncharacterized

 

FAM161A

2785

retinal disease

25749990

TMEM214

1190

uncharacterized

 

FAM227A

4981

cancer

26759717

TMEM50B

1026

uncharacterized

 

FAM84B

3626

tumorogenesis

25980316

TMEM56

1243

nicotine dependence

20379614

FBLIM1

2126

breast cancer,

23645746

TMF1

4736

prostate cancer

19330832

FBXL22

1411

cardiomyopathy

24324551

TMOD2

7816

bladder cancer

15095301

FBXO27

1535

leukemia

126433

TNFRSF10A

1621

cancer

27780136

FGD4

7619

cancer

22589722

TNFRSF10D

1532

cancer

26542757

FKBP14

1515

ovarian cancer

27931282

TOP3A

3814

leukaemia

22050635

FKBP14

2129

TPRG1L

1754

uncharacterized

 

FKBP5

7114

schizophrenia

25522420

TRIM72

1885

ischemia

26790476

FXN

3288

metabolic disease

26717909

TRPM7

8079

neuroblastoma

27402209

GDPD1

1559

phosphodiesterase

18991142

TRPM7

8221

carcinoma

26779625

GEMIN8

2172

neuropathy

16434402

TXNDC15

2460

thrombosis

21642008

GGT6

1956

ovarian cancer

25356737

TYW5

3692

schizophrenia

23974872

GK5

3808

glioblastoma

25936394

UACA

6120

lung cancer

22407486

GK5

6355

glioblastoma

25936394

UACA

6120

thyroid diseases

15358194

GLB1L

2224

phosphatase

21382349

UBIAD1

2881

cancer

23759948

GOLGA3

7240

immune disease

17711851

UBXN2A

1665

colon cancer

24625977

GP2

1877

crohn disease

22891285

UPK1B

1513

cancer

16354592,

GPR65

3309

tumorogenesis

24152439

UQCRB

1269

colorectal cancer

22545919

GPR65

3309

immune diseases

15665078

USP29

2*

protease

10958632

GPR82

2664

uncharacterized

 

VHL

3764

tumorogenesis

27460078

GPRIN2

6676

schizophrenia

27244233

VHL

3898

 

GTPBP10

1873

prostate cancer

27409348

VWA2

3366

colon cancer

15580307

H6PD

5754

tumorogenesis

15221007

WDR73

1736

microcephaly

25466283

HM13

1745

glioblastoma

28198167

XIAP

5681

ovarian cancer

26779627

IFIT3

1864

pancreatic cancer

25650658

YAE1D1

1548

oral cancer

23318452

ISY1

686**

uncharacterized

 

ZBTB24

4842

hepatocarcinoma

27730394

IYD

1658

hypothyroidism.

18765512

ZC3H12D

2812

Acute lung injury

26059755

KIAA1456

2536

colorectal cancer

24743840

ZDHHC20

3390

tumorogenesis

20334580

KIF11

3598

tumorogenesis

28011472

ZFP30

3463

hypertension

19851296

KLHL23

2570

tumorogenesis

23676014

ZNF114

1827

transcription factor

8467795

KPNA1

5711

breast cancer

26052702

ZNF197

3446

thyroid cancer

12682018

KREMEN1

2199

schizophrenia

20153141

ZNF320

5534

glioblastoma

11536051

KREMEN1

2792

schizophrenia

20153141

ZNF429

2081**

transcription factor

7865130

LAX1

2057

uncharacterized

 

ZNF445

8820

transcription factor

16368201

LILRA6

2201

tumorogenesis

26769854

ZNF461

3087

transcription factor

15004467

LIMD1

5735

breast cancer

27656835

ZNF549

3736

transcription factor

16344560

LIMS1

3931

cancer

27590440

ZNF557

4791

transcription factor

15851553

LMOD3

3224

myopathy

25250574

ZNF626

4620

liver diseases

18255255

LMOD3

3993

Alzheimer’s D

22881374

ZNF667

3240

transcription factor

17397802

METTL6

1188

breast cancer

25151356

ZNF716

2799

cardiovascular D

24376456

MR1

3664

hepatocarcinoma

26823810

ZNF780B

5415

transcription factor

15057824

MREG

1540

pulmonary D

20463177

ZNF84

4920

transcription factor

11856868

    

ZNF841

3422

transcription factor

24280104

Notes: * - 5’UTR, **- CDS; others – 3’UTR, D - disease

The mRNAs of 201 human genes have complete complementary binding sites of miR-619-5p in the 3’UTR (214 sites), CDS (3 sites), and 5’UTR (4 sites). The mRNAs of 27 genes have four binding sites, seven genes have five binding sites, and CATAD1, ICA1L, GK5, POLH, and PRR11 genes have six miR-619-5p binding sites. The mRNAs of OPA3 and CYP20A1 genes have eight and ten binding sites, respectively. All of these sites are located in the 3’UTRs of mRNAs.

The target genes of the miR-619-5p carry out one or more different functions and are involved in the development of various diseases (Table 1).

The mRNAs of the C17orf75, C8orf44, CIAO1, CPM, CYP20A1, DCAF10, FKBP14, RAB3IP, SYNJ2BP, VHL genes have two complete complementary binding sites for miR-619-5p, and the mRNA of the CACNG8 gene has three such binding sites. This indicates a stronger dependence of the expression of these genes on miR-619-5p.

One of the methods to establish the credibility of the presence of miRNA binding site in the mRNA is to verify this site in the mRNAs of orthologous genes. In finding the miRNA binding sites raises the question of the level of reliability of the found sites. One effective way to establish the credibility of the binding sites is to establish binding sites in the orthologous genes and the identification of orthologous miRNA. Location of binding site in the protein coding region facilitates its conservation in evolution, especially if the corresponding oligopeptide plays an important role in the function of the protein. miR-619-5p binding sites with complete complementarity (ΔG/ΔGm is 100%) to the mRNAs of the four genes are located in the 5’UTRs (Table 2).
Table 2

Variation of positions and nucleotide sequences of miR-619-5p binding sites in the 5’UTRs of mRNAs of mammal genes

Species

Gene

Position

of site, nt

Nucleotide sequence

Hsa

CCDC114

261

GCAUGCUGGCUCAUGCCUGUAAUCCCAGCACUUUGG

Hsa

DHRS9

1281

GCGCGGUGGCUCAUGCCUGUAAUCCCAGCACUUUGG

Hsa

RGS3

205

GCGCAGUGGCUCAUGCCUGUAAUCCCAGCACUUUGG

Ptr

RGS3

1

GCGCAGUGGCUCAUGCCUGUAAUCCCAGCACUUUGG

Nle

RGS3

205

GCACGGUGGCUCAUGCCUGUAAUCCCAGCACUUUGG

Hsa

USP29

2

CUGGCCAGGCUCAUGCCUGUAAUCCCAGCACUUUGG

Pab

USP29

52

CUGGCCAGGCUCAUGCCUGUAAUCCCAGCACUUUGG

Nle

USP29

52

CUGGCCAGGCUCAUGCCUGUAAUCCCAGCACUUUGG

Mle

USP29

47

CUGGCCAGGCUCAUGCCUGUAAUCCCAGCACUUUGG

Can

USP29

98

CUGGCCAGGCUCAUGCCUGUAAUCCCAGCAUUUUGG

Ggo

USP29

100

CUGGCCAGGCUCAUGCCUGUAAUUCCAGCACUUUGG

Rro

USP29

52

CUGGCCAGGCUCAUGCCUGUAAUCGCAGCACUUUGG

Notes: In the table 2-5 the bold type indicates the binding site of miR-619-5p

Before the 5’ end and after the 3’ end of miR-619-5p binding site, nucleotides are not homologous. The mRNAs of RGS3 and USP29 orthologous genes have binding sites in H. sapiens, N. leucogenys, P. abelii, M. leucophaeus, C. angolensis palliatus, G. gorilla, and R. roxellana.

miR-619-5p has two binding sites in the 5’UTRs of mRNAs of ANAPC16, CYB5D2, and PRR5 and three binding sites in the mRNA of DNASE1.

mRNAs of some genes have binding sites for miR-619-5p within their 5’UTRs and 3’UTRs or CDSs and 3’UTRs. For example, ATAD3C, C14orf182, and CYB5RL have miR-619-5p binding sites in the 5’UTRs and 3’UTRs, and C8orf44, ISY1, and ZNF714 have miR-619-5p binding sites in the CDSs and 3’UTRs.

The nucleotide sequences of miR-619-5p binding sites are located in the CDSs of the C8orf44, C8H8orf44, ISY1, ZNF429, and ZNF714 genes and encode the following oligopeptides (Table 3).
Table 3

Variation of amino acid sequences coding in miR-619-5p binding sites in the mRNAs of orthologous genes

Species

Gene

Amino acid sequence

Hsa

C8orf44

HWKGRARWLMPVIPALWEAKA

Hsa

C8H8orf44

HWKGRARWLMPVIPALWEAKA

Pab

C8H8orf44

HWKGWARWLTPVIPALWEAKA

Pan

C8H8orf44

HWKGRARWLMPAIPALWEAKX

Ppa

C8H8orf44

HWKGRAQWLTPVIPALWEAKA

Ptr

C8H8orf44

HWKGRAQWLTPVIPALWEAKA

Hsa

ISY1

EKERQVRWLMPVIPALWEAEA

Hsa

ZNF714

KIQQGMVAHACNPNTLRGLGE

Ggo

ZNF714

KIQQGMVAHACNPNTLRGLGE

Ptr

ZNF714

KIQQGMVAHACNPNTXRGLGE

Ppa

ZNF714

KIQQGMVAHACNPNTLRGLGE

Hsa

ZNF429

IHRMGVVAHACNPSTLGGRGG

Mfa

ZNF429

IHRLGVVAHACNPSTLGGRGG

Mmu

ZNF429

IHRLGVVAHACNPSTLGGRGG

Mne

ZNF429

IHRLGVVAHACNPSTLGGRGG

C8H8orf44, C8orf44, and ISY1 genes encode the WLMPVIP oligopeptide, which is also present in the orthologous proteins of P. abelii, P. anubis, P. paniscus, and P. troglodytes. The mRNA of transcription factor ZNF429 and ZNF429 genes binding sites are encoded the AHACNP oligopeptide in the another reading frame. The first two oligopeptides are encoded in one open reading frame (ORF) and the amino acid sequences are highly conserved. The homologous oligonucleotide of the miR-619-5p binding site in the mRNA of ZNF714 gene codes for an oligopeptide in a different ORF.

The presence of miR-619-5p binding sites in the CDSs of five genes with different functions and the evolutionary conservation of these sites signify the role of miRNA in the regulation of the expression of these genes. The nucleotide sequences of specific regions of mRNAs of C8H8orf44, C8orf44, ISY1, ZNF429, and ZNF714 genes that contain miR-619-5p binding sites in the CDSs are homologous among themselves and to the binding sites located in the 5’UTRs and 3’UTRs.

The miRNA binding sites in the coding region, as opposed to the 3’UTR and 5’UTR, clearly demonstrate the relationship between miRNA and mRNA by their conserved amino acid sequences in orthologous proteins. miRNA binding site can be translated by two open reading frames that encode WLTPVIPA and AHACNPS oligopeptides. In the third reading frame, the miR-619-5p binding site has a stop codon. However, in the genes studied, no such sequence was found. In the absence of complete complementarity between miR-619-5p and its binding site, miR-619-5p uses a site containing the corresponding mutation in the CDS for the regulation of gene expression. Thus, a single miRNA binding site in the mRNA of various genes may correspond to three different oligopeptides. Generally, one out of these three oligopeptides is present in the proteins encoded by the orthologous genes.

ISY1 orthologous genes in H. sapiens, P. troglodytes, and N. leucogenys encode a protein containing QVRWLMPVIPALWEAEAGGSQA oligopeptide sequence (Table 4).
Table 4

Amino acid sequences coding in miR-619-5p binding sites in the mRNA of ISY1 gene of orthologous genes

Species

Amino acid sequence

Hsa

PGVRELFEKERQVRWLMPVIPALWEAEAGGSQALPPPRKTRAELMKA

Ptr

PGVRELFEKERQVRWLMPVIPALWEAEAGGSQALPPPRKTRAELMKA

Nle

PGVRELFEKERQARWLTPVIPALWEAEAGGSQALPPPRKTRAELMKA

Hsa*

PGVRELFEKEP----------------------LPPPRKTRAELMKA

Bmu

PGVRELFEKEP----------------------LPPPRKTRAELMKA

Cdr

PGVRELFEKEP----------------------LPPPRKTRAELMKA

Cfa

PGVRELFEKEP----------------------LPPPRKTRAELMKA

Cja

PGVRELFEKEP----------------------LPPPRKTRAELMKA

Eca

PGVRELFEKEP----------------------LPPPRKTRAELMKA

Ggg

PGVRELFEKEP----------------------LPPPRKTRAELMKA

Mmu

PGVRELFEKEP----------------------LPPPRKTRAELMKA

Nle

PGVRELFEKEP----------------------LPPPRKTRAELMKA

Oar

PGVRELFEKEP----------------------LPPPRKTRAELMKA

Pab

PGVRELFEKEP----------------------LPPPRKTRAELMKA

Ppa

PGVRELFEKEP----------------------LPPPRKTRAELMKA

Rro

PGVRELFEKEP----------------------LPPPRKTRAELMKA

* RAB43 - human ISY1 paralog gene

However, the RAB43 gene, which is paralogous to human ISY1, lacks the nucleotide sequence encoding the QVRWLMPVIPALWEAEAGGSQA oligopeptide. Additionally, ISY1 gene in the genomes of other animals also lacks the nucleotide sequence encoding this oligopeptide (Table 4).

Nucleotide sequences of miR-619-5p binding sites in the mRNAs of ADAM17, ALDH3A2, and ARL11 orthologous genes are shown in Table 5.
Table 5

Variation of nucleotide sequences of miR-619-5p binding sites in the 3’UTR of mRNAs of ADAM17, ALDH3A2, and ARL11 of orthologs

Species

Gene

Position, nt

Nucleotide sequence

Hsa

ADAM17

3466

TGGGAGTGGTGGCTCATGCCTGTAATCCCAGCACTTGGAGAGG

Cat

ADAM17

3485

GGGGCGCAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG

Mmul

ADAM17

3491

GGGGCGCGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG

Mne

ADAM17

3438

GGGGCGCGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG

Ptr

ADAM17

3449

TGGGAGTGGTGGCTCATGCCTGTAATCCCAGCACTTGGAGAGG

Rro

ADAM17

3425

GGGGCGCGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG

Hsa

ALDH3A2

2617

CGGGCGTGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG

Cja

ALDH3A2

3444

CGGGCGTGGTGGCTCATGCCTGTAATCCCAGCACTTTAGGAGG

Ggo

ALDH3A2

2712

CGGGCGTGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG

Mmul

ALDH3A2

2509

CGGACATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG

Mne

ALDH3A2

2504

CGGACATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG

Nle

ALDH3A2

2714

TGGTCATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG

Pab

ALDH3A2

2297

TGGGCATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG

Ppa

ALDH3A2

2715

CGGGCATGGTGGCTCATGTCTGTAATCCCAGCACTTTGGGAGG

Ptr

ALDH3A2

2711

CGGGCATGGTGGCTCATGTCTGTAATCCCAGCACTTTGGGAGG

Rro

ALDH3A2

2727

CGGACGTGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG

Hsa

ARL11

1033

TTGGCCCGGTGGCTCATGCCTGTAATCCCAGCACTGTGGGAGA

Cat

ARL11

1642

CAGATGCAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGTGG

Mfa

ARL11

1698

CAGATGCAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGTGG

Mmul

ARL11

1747

CAGATGCAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGTGG

Mne

ARL11

1024

TTGGCACGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGA

Mne

ARL11

1471

CAGATGCAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGTGG

Ptr

ARL11

1353

CGGGCATGGTGGCTCATGTCTGTAATCCCAGCACTTTGGGAGG

Rro

ARL11

1254

CAGGTGCAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGCGG

These orthologous genes are characterized by highly conserved nucleotide sequence GGCTCATGCCTGTAATCCCAGC of miR-619-5p binding sites. This shows that the interaction of miR-619-5p with mRNAs of these genes is conserved during evolution. Some of the human miR-619-5p target genes and their corresponding orthologous genes have two miR-619-5p binding sites in their mRNAs.

Table 6 shows the nucleotide sequences of two miR-619-5p binding sites in the 3’UTR of mRNAs of ERBB3, FBLIM1, and FKBP14 orthologous genes.
Table 6

Variation of nucleotide sequences of two miR-619-5p binding sites in the 3’UTR of mRNAs of ERBB3, FBLIM1, and FKBP14 of orthologs

Species

Gene

Position, nt

Nucleotide sequence

Hsa

ERBB3

4950

CGGGCATGGTGGCTCATGCCTGTAATCTCAGCACTTTGGGAG

Hsa

ERBB3

5104

TGGGTGCAGTGGCTCATGCCTGTAATCCCAGCCAGCACTTTG

Csa

ERBB3

4989

CGGGCATGGTGGCTCATGCCTGTAATCCTAGCACTTTGGGAG

Csa

ERBB3

5149

TGGGCGCTGTGGCTCATGCCTGCAATCCCAGCACTTTGGGAG

Mfa

ERBB3

5114

TGGGCATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAG

Mfa

ERBB3

5269

TGGGCGCTGTGGCTCATGCCTGCAATCCCAGCCCTTTGGGAG

Mmu

ERBB3

5114

TGGGCATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAG

Mmu

ERBB3

5269

TGGGCGCTGTGGCTCATGCCTGCAATCCCAGCCCTTTGGGAG

Mne

ERBB3

5112

CGGGCATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAG

Mne

ERBB3

5267

TGGGCGCTGTGGCTCATGCCTGCAATCCCAGCCCTTTGGGAG

Pan

ERBB3

5106

CGGGCATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAG

Pan

ERBB3

5274

TGGGCGCTGTGGCTCATGCCTGCAGTCCCAGCACTTTGGGAG

Ptr

ERBB3

5105

CGGGCATGGTGGCTCATGCCTGTAATCTCAGCACTTTGGGAG

Ptr

ERBB3

5243

TGGGTGCAGTGGCTCATGCCTGTAATCCCAGCCAGCACTTTG

Mne

FBLIM1

1938

TGGGCGTGGTGGCTCATGCCTGTAATCCCTGCACTTTGGGAG

Mne

FBLIM1

5267

TGGGCGCTGTGGCTCATGCCTGCAATCCCAGCCCTTTGGGAG

Pab

FKBP14

1514

CAGGCACGGTGGCTCACGCCTGTAATCCCAGCACTTCGGGAG

Pab

FKBP14

2128

TGGGTGTGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGGG

Notes: The black type indicates the binding site of miR-619-5p

Table 7 shows the degree of conservation of miR-619-5p binding sites in the 201 mRNAs of target genes. All mRNAs with complete complementarity to miR-619-5p binding sites (ΔG/ΔGm is 100%) were divided into four groups, and the frequency of occurrence of nucleotides was determined in each group. The results suggest that miR-619-5p binding sites are highly conserved. The binding site GGCTCATGCCTGTAATCCCAGC does not change and in each of the four gene groups the observed variability of nucleotides on the right and left is high.
Table 7

Variation of nucleotide sequences of mRNA region with miR-619-5p binding sites (See Additional file 1, 2, 3 and 4)

Discussion

Here we have identified many miRNAs binding sites in the mRNAs of 201 human genes which indicates that umiRNAs act as coordinators of gene expression by participating in many biological processes. Previous studies have shown the influences of miRNAs on the expression of genes that encode the transcription factors [19, 20] and on the expression of proteins that participate in the cellular cycle [3, 2123], apoptosis [4, 2426], and stress responses [27]. It was shown the role of the mir-619-5p in the regulation of different pathological processes [28]. It was investigated the correlations between the expression of MALAT1 and miR-619-5p, in addition to the association between the clinicopathological features and survival outcomes of patients with stage II and III colorectal cancer tumors [28]. It was observed, that hsa-miR-619-5p and hsa-miR-1184 microRNA expression significantly increased in prostatic cancer. MicroRNA-gene-net analysis indicated that miR-619-5p and other some miRNAs had the most important and extensive regulatory function for Qi-stagnation syndromes and Qi-deficiency syndromes in coronary heart disease [29].

One or several umiRNAs regulating the expression of hundreds of genes can create a system of interconnected processes in cells and organisms. Such role of these umiRNAs is possible because they circulate in the blood and have access to nearly all cells of an organism [3032]. Our results provide the basis for studying the systemic roles of unique and normal miRNAs in the regulation of gene expression in human cells. The expression of many target genes is regulated by umiRNAs does not allow individual mRNAs of target genes to be expressed in more degree than others. The greater expression of one mRNA, the larger number of umiRNAs bind to this mRNA. This allows one umiRNA to maintain a certain balance of expression of the corresponding target genes. If umiRNA expression changes, such system is vulnerable. This will cause the development of pathology in the cell, tissue or body.

Conclusions

The majority of miR-619-5p binding sites are located in the 3’UTRs of mRNAs of target genes. Some genes have miRNA binding sites in the 5’UTRs of mRNAs. It is necessary to maintain nucleotide sequences of the binding site of umiRNA in the CDSs of several genes. Different genes have binding sites for miRNAs that are read in different open reading frames. Therefore, identical nucleotide sequences encode different amino acids in different proteins. In encoded proteins, these sites encode conservative oligopeptides. The binding sites of miR-619-5p in 3’UTRs, 5’UTRs and CDSs are conservative in the orthologous mammalian genes.

Abbreviations

CDSs: 

Coding domain sequences

miRNAs: 

Micrornas

ORF: 

Open reading frame

Umirna: 

Unique miRNA

Declarations

Acknowledgements

We thank Leducq foundation and the European Union project «Muscle Stress Relief». Also we thank PhD Berillo O. for her help in the collection of data.

Funding

This study was supported by a grant (N0491/ГФ4) from the Ministry of Education and Science, Kazakhstan Republic, SRI of Biology and Biotechnology Problems, al-Farabi Kazakh National University, and Institute for Anesthesiology and Intensive Operative Care Medical Faculty Mannheim, Mannheim, Germany.

Availability of data and materials

The data sets supporting the results of this article are included within the article and its additional files and publicly available.

Authors’ contributions

SA, RN and AI conceived of the study and drafted the manuscript. SA, RN, AI, SL, AP, IP and AA made substantial contributions to acquisition of data, to interpretation and modification of the data. All authors involved in drafting the manuscript, read and approved the final version of the manuscript.

Competing interests

The authors declares that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
SRI Of Biology and Biotechnology Problems, Al-Farabi Kazakh National University
(2)
Institute for Anaesthesiology and Intensive Operative Care Medical Faculty Mannheim

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© The Author(s). 2017