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Functional study of one nucleotide mutation in pri-miR-125a coding region which related to recurrent pregnancy loss.

Hu Y, Huo ZH, Liu CM, Liu SG, Zhang N, Yin KL, Qi L, Ma X, Xia HF - PLoS ONE (2014)

Bottom Line: In this study, we identified a new mutation site (+29A>G, position relative to pre-miR-125a) by scanning pri-miR-125a coding region in 389 Chinese Han RPL patients.Subsequent in vitro analysis indicated that the A>G mutation reduced mature miR-125a expression, and further led to less efficient inhibition of verified target genes.These data suggest that A>G mutation in pri-miR-125a coding region contributes to the genetic predisposition to RPL by disordering the production of miR-125a, which consequently meddled in gene regulatory network between mir-125a and mRNA.

View Article: PubMed Central - PubMed

Affiliation: Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China; Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

ABSTRACT
MicroRNAs (miRNAs) are short non-coding RNAs which modulate gene expression by binding to complementary segments present in the 3'UTR of the mRNAs of protein coding genes. MiRNAs play very important roles in maintaining normal human body physiology conditions, meanwhile, abnormal miRNA expressions have been found related to many human diseases spanning from psychiatric disorders to malignant cancers. Recently, emerging reports have indicated that disturbed miRNAs expression contributed to the pathogenesis of recurrent pregnancy loss (RPL). In this study, we identified a new mutation site (+29A>G, position relative to pre-miR-125a) by scanning pri-miR-125a coding region in 389 Chinese Han RPL patients. This site was co-existed with two polymorphisms (rs12976445 and rs41275794) in patients heterogeneously and changed the predicted secondary structures of pri-miR-125a. Subsequent in vitro analysis indicated that the A>G mutation reduced mature miR-125a expression, and further led to less efficient inhibition of verified target genes. Functional analysis showed that mutant pri-mir-125a can enhance endometrial stromal cells (ESCs) invasive capacity and increase the sensitivity of ESCs cells to mifepristone. Moreover, we further analyzed the possible molecular mechanism by RIP-chip assay and found that mutant pri-mir-125a disturbed the expression of miR-125a targetome, the functions of which includes embryonic development, cell proliferation, migration and invasion. These data suggest that A>G mutation in pri-miR-125a coding region contributes to the genetic predisposition to RPL by disordering the production of miR-125a, which consequently meddled in gene regulatory network between mir-125a and mRNA.

No MeSH data available.


Related in: MedlinePlus

GO analysis of the genes enriched in RISC in mutant genotype group.Genes enriched in RISC in mutant genotype were analyzed use David online tools. The GO terms were listed on the left from down to up according P value from small to large.
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pone-0114781-g006: GO analysis of the genes enriched in RISC in mutant genotype group.Genes enriched in RISC in mutant genotype were analyzed use David online tools. The GO terms were listed on the left from down to up according P value from small to large.

Mentions: To assign biological meaning to the group of genes with changed enrichment, the subset of genes which met the above criteria were analyzed with the Gene Ontology (GO) classification system, using DAVID software (http://apps1.niaid.nih.gov/david/) [14]. Overrepresentation of genes with altered expression within specific GO categories was determined using the Fisher exact test (P<0.05). After GO analysis we found 9 embryo development related genes (PTK7, CHD8, GRN, TAB1, NDEL1, RBBP8, PSMC4, TSC2, and VANGL2) enriched in RISC complex in the mutation group, which means the expression of those genes should be more seriously repressed than the normal genotype cells(Table S1). As shown in Fig. 6, highlighted by red box, their functions involve blastocyst hatching, blastocyst development, neural tube closure, in utero embryonic development and so on.


Functional study of one nucleotide mutation in pri-miR-125a coding region which related to recurrent pregnancy loss.

Hu Y, Huo ZH, Liu CM, Liu SG, Zhang N, Yin KL, Qi L, Ma X, Xia HF - PLoS ONE (2014)

GO analysis of the genes enriched in RISC in mutant genotype group.Genes enriched in RISC in mutant genotype were analyzed use David online tools. The GO terms were listed on the left from down to up according P value from small to large.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4257728&req=5

pone-0114781-g006: GO analysis of the genes enriched in RISC in mutant genotype group.Genes enriched in RISC in mutant genotype were analyzed use David online tools. The GO terms were listed on the left from down to up according P value from small to large.
Mentions: To assign biological meaning to the group of genes with changed enrichment, the subset of genes which met the above criteria were analyzed with the Gene Ontology (GO) classification system, using DAVID software (http://apps1.niaid.nih.gov/david/) [14]. Overrepresentation of genes with altered expression within specific GO categories was determined using the Fisher exact test (P<0.05). After GO analysis we found 9 embryo development related genes (PTK7, CHD8, GRN, TAB1, NDEL1, RBBP8, PSMC4, TSC2, and VANGL2) enriched in RISC complex in the mutation group, which means the expression of those genes should be more seriously repressed than the normal genotype cells(Table S1). As shown in Fig. 6, highlighted by red box, their functions involve blastocyst hatching, blastocyst development, neural tube closure, in utero embryonic development and so on.

Bottom Line: In this study, we identified a new mutation site (+29A>G, position relative to pre-miR-125a) by scanning pri-miR-125a coding region in 389 Chinese Han RPL patients.Subsequent in vitro analysis indicated that the A>G mutation reduced mature miR-125a expression, and further led to less efficient inhibition of verified target genes.These data suggest that A>G mutation in pri-miR-125a coding region contributes to the genetic predisposition to RPL by disordering the production of miR-125a, which consequently meddled in gene regulatory network between mir-125a and mRNA.

View Article: PubMed Central - PubMed

Affiliation: Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China; Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

ABSTRACT
MicroRNAs (miRNAs) are short non-coding RNAs which modulate gene expression by binding to complementary segments present in the 3'UTR of the mRNAs of protein coding genes. MiRNAs play very important roles in maintaining normal human body physiology conditions, meanwhile, abnormal miRNA expressions have been found related to many human diseases spanning from psychiatric disorders to malignant cancers. Recently, emerging reports have indicated that disturbed miRNAs expression contributed to the pathogenesis of recurrent pregnancy loss (RPL). In this study, we identified a new mutation site (+29A>G, position relative to pre-miR-125a) by scanning pri-miR-125a coding region in 389 Chinese Han RPL patients. This site was co-existed with two polymorphisms (rs12976445 and rs41275794) in patients heterogeneously and changed the predicted secondary structures of pri-miR-125a. Subsequent in vitro analysis indicated that the A>G mutation reduced mature miR-125a expression, and further led to less efficient inhibition of verified target genes. Functional analysis showed that mutant pri-mir-125a can enhance endometrial stromal cells (ESCs) invasive capacity and increase the sensitivity of ESCs cells to mifepristone. Moreover, we further analyzed the possible molecular mechanism by RIP-chip assay and found that mutant pri-mir-125a disturbed the expression of miR-125a targetome, the functions of which includes embryonic development, cell proliferation, migration and invasion. These data suggest that A>G mutation in pri-miR-125a coding region contributes to the genetic predisposition to RPL by disordering the production of miR-125a, which consequently meddled in gene regulatory network between mir-125a and mRNA.

No MeSH data available.


Related in: MedlinePlus