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Identi?cation of a novel antisense RNA that regulates growth hormone receptor expression in chickens.

ABSTRACT: Natural antisense transcripts (NATs) are widely present in mammalian genomes and act as pivotal regulator molecules of gene expression. However, studies on NATs in the chicken are relatively rare. We identi?ed a novel antisense transcript in the chicken, designated GHR-AS-EST, transcribed from the growth hormone receptor (GHR) locus, which encodes a well-known regulatory molecule of muscle development and fat deposition. GHR-AS-EST is predominantly expressed in the chicken liver and muscle tissues. GHR-AS-EST sequence conservation among vertebrates is weak. GHR-AS-EST forms an RNA-RNA duplex with GHBP to increase its stability, and regulates the expression of GHR sense transcripts at both the mRNA and protein levels. Further, GHR-AS-EST promotes cell proliferation by stimulating the expression of signaling factors in the JAK2/STAT pathway, and contributes to fat deposition via downregulating the expression of signaling factors in the JAK2/SOCS pathway in LMH hepatocellular carcinoma cells. We expect that the discovery of a NAT for a regulatory gene associated with cell proliferation and lipolysis will further our understanding of the molecular regulation of both muscle development and fat deposition.

SUBMITTER: Lin S

PROVIDER: S-EPMC6546403 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Identiﬁcation of a novel antisense RNA that regulates growth hormone receptor expression in chickens.

Lin Shudai S Zhang Zihao Z Xie Tingting T Hu Bowen B Ruan Zhuohao Z Zhang Li L Li Congjun C Li Charles C Luo Wen W Nie Qinghua Q Zhang Xiquan X

RNA biology 20190214 5

Natural antisense transcripts (NATs) are widely present in mammalian genomes and act as pivotal regulator molecules of gene expression. However, studies on NATs in the chicken are relatively rare. We identiﬁed a novel antisense transcript in the chicken, designated GHR-AS-EST, transcribed from the growth hormone receptor (GHR) locus, which encodes a well-known regulatory molecule of muscle development and fat deposition. GHR-AS-EST is predominantly expressed in the chicken liver and muscle tissu ...[more]

PMID: 30764709

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Project description:BACKGROUND: A deletion mutation in the growth hormone receptor (GHR) gene results in the inhibition of skeletal muscle growth and fat deposition in dwarf chickens. We used microarray techniques to determine microRNA (miRNA) and mRNA expression profiles of GHR in the skeletal muscles of 14-day-old embryos as well as 7-week-old deletion-type dwarf and normal-type chickens. Our aim was to elucidate the miRNA regulation of GHR expression with respect to growth inhibition and fat deposition. RESULTS: At the same developmental stages, different expression profiles in skeletal muscles of dwarf and normal chickens occurred for four miRNAs (miR-1623, miR-181b, let-7b, and miR-128). At different developmental stages, there was a significant difference in the expression profiles of a greater number of miRNAs. Eleven miRNAs were up-regulated and 18 down-regulated in the 7-week-old dwarf chickens when compared with profiles in 14-day-old embryos. In 7-week-old normal chickens, seven miRNAs were up-regulated and nine down-regulated compared with those in 14-day-old embryos. In skeletal muscles, 22 genes were up-regulated and 33 down-regulated in 14-day-old embryos compared with 7-week-old dwarf chickens. Sixty-five mRNAs were up-regulated and 108 down-regulated in 14-day-old embryos as compared with 7-week-old normal chickens. Thirty-four differentially expressed miRNAs were grouped into 18 categories based on overlapping seed and target sequences. Only let-7b was found to be complementary to its target in the 3' untranslated region of GHR, and was able to inhibit its expression. Kyoto Encyclopedia of Genes and Genomes pathway analysis and quantitative polymerase chain reactions indicated there were three main signaling pathways regulating skeletal muscle growth and fat deposition of chickens. These were influenced by let-7b-regulated GHR. Suppression of the cytokine signaling 3 (SOCS3) gene was found to be involved in the signaling pathway of adipocytokines. CONCLUSIONS: There is a critical miRNA, let-7b, involved in the regulation of GHR. SOCS3 plays a critical role in regulating skeletal muscle growth and fat deposition via let-7b-mediated GHR expression.

Project description:Transcription is regulated by a complex interaction of activators and repressors. The effectors of repression are large multimeric complexes which contain both the repressor proteins that bind to transcription factors and a number of co-repressors that actually mediate transcriptional silencing either by inhibiting the basal transcription machinery or by recruiting chromatin-modifying enzymes.TBLR1 [GenBank: NM024665] is a co-repressor of nuclear hormone transcription factors. A single highly conserved gene encodes a small family of protein molecules. Different isoforms are produced by differential exon utilization. Although the ORF of the predominant form contains only 1545 bp, the human gene occupies approximately 200 kb of genomic DNA on chromosome 3q and contains 16 exons. The genomic sequence overlaps with the putative DC42 [GenBank: NM030921] locus. The murine homologue is structurally similar and is also located on Chromosome 3. TBLR1 is closely related (79% homology at the mRNA level) to TBL1X and TBL1Y, which are located on Chromosomes X and Y. The expression of TBLR1 overlaps but is distinct from that of TBL1. An alternatively spliced form of TBLR1 has been demonstrated in human material and it too has an unique pattern of expression. TBLR1 and the homologous genes interact with proteins that regulate the nuclear hormone receptor family of transcription factors. In resting cells TBLR1 is primarily cytoplasmic but after perturbation the protein translocates to the nucleus. TBLR1 co-precipitates with SMRT, a co-repressor of nuclear hormone receptors, and co-precipitates in complexes immunoprecipitated by antiserum to HDAC3. Cells engineered to over express either TBLR1 or N- and C-terminal deletion variants, have elevated levels of endogenous N-CoR. Co-transfection of TBLR1 and SMRT results in increased expression of SMRT. This co-repressor undergoes ubiquitin-mediated degradation and we suggest that the stabilization of the co-repressors by TBLR1 occurs because of a novel mechanism that protects them from degradation. Transient over expression of TBLR1 produces growth arrest.TBLR1 is a multifunctional co-repressor of transcription. The structure of this family of molecules is highly conserved and closely related co-repressors have been found in all eukaryotic organisms. Regulation of co-repressor expression and the consequent alterations in transcriptional silencing play an important role in the regulation of differentiation.

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Identi?cation of a novel antisense RNA that regulates growth hormone receptor expression in chickens.

Publications

Identiﬁcation of a novel antisense RNA that regulates growth hormone receptor expression in chickens.

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