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Ontogeny, conservation and functional significance of maternally inherited DNA methylation at two classes of non-imprinted genes.

ABSTRACT: A functional role for DNA methylation has been well-established at imprinted loci, which inherit methylation uniparentally, most commonly from the mother via the oocyte. Many CpG islands not associated with imprinting also inherit methylation from the oocyte, although the functional significance of this, and the common features of the genes affected, are unclear. We identify two major subclasses of genes associated with these gametic differentially methylated regions (gDMRs), namely those important for brain and for testis function. The gDMRs at these genes retain the methylation acquired in the oocyte through preimplantation development, but become fully methylated postimplantation by de novo methylation of the paternal allele. Each gene class displays unique features, with the gDMR located at the promoter of the testis genes but intragenically for the brain genes. Significantly, demethylation using knockout, knockdown or pharmacological approaches in mouse stem cells and fibroblasts resulted in transcriptional derepression of the testis genes, indicating that they may be affected by environmental exposures, in either mother or offspring, that cause demethylation. Features of the brain gene group suggest that they might represent a pool from which many imprinted genes have evolved. The locations of the gDMRs, as well as methylation levels and repression effects, were also conserved in human cells.

SUBMITTER: Rutledge CE

PROVIDER: S-EPMC3943183 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Ontogeny, conservation and functional significance of maternally inherited DNA methylation at two classes of non-imprinted genes.

Rutledge Charlotte E CE Thakur Avinash A O'Neill Karla M KM Irwin Rachelle E RE Sato Shun S Hata Ken K Walsh Colum P CP

Development (Cambridge, England) 20140212 6

A functional role for DNA methylation has been well-established at imprinted loci, which inherit methylation uniparentally, most commonly from the mother via the oocyte. Many CpG islands not associated with imprinting also inherit methylation from the oocyte, although the functional significance of this, and the common features of the genes affected, are unclear. We identify two major subclasses of genes associated with these gametic differentially methylated regions (gDMRs), namely those import ...[more]

PMID: 24523459

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Project description:BackgroundMicroRNAs play an important functional role in post-transcriptional gene regulation. One of the largest known microRNA clusters is located within the imprinted Dlk1/Gtl2 region on human chromosome 14 and mouse chromosome 12. This cluster contains more than 40 microRNA genes that are expressed only from the maternal chromosome in mouse.ResultsTo shed light on the function of these microRNAs and possible crosstalk between microRNA-based gene regulation and genomic imprinting, we performed extensive in silico analyses of the microRNAs in this imprinted region and their predicted target genes.Bioinformatic analysis reveals that these microRNAs are highly conserved in both human and mouse. Whereas the microRNA precursors at this locus mostly belong to large sequence families, the mature microRNAs sequences are highly divergent. We developed a target gene prediction approach that combines three widely used prediction methods and achieved a sufficiently high prediction accuracy. Target gene sets predicted for individual microRNAs derived from the imprinted region show little overlap and do not differ significantly in their properties from target genes predicted for a group of randomly selected microRNAs. The target genes are enriched with long and GC-rich 3' UTR sequences and are preferentially annotated to development, regulation processes and cell communication. Furthermore, among all analyzed human and mouse genes, the predicted target genes are characterized by consistently higher expression levels in all tissues considered.ConclusionOur results suggest a complex evolutionary history for microRNA genes in this imprinted region, including an amplification of microRNA precursors in a mammalian ancestor, and a rapid subsequent divergence of the mature sequences. This produced a broad spectrum of target genes. Further, our analyses did not uncover a functional relation between imprinted gene regulation of this microRNA-encoding region, expression patterns or functions of predicted target genes. Specifically, our results indicate that these microRNAs do not regulate a particular set of genes. We conclude that these imprinted microRNAs do not regulate a particular set of genes. Rather, they seem to stabilize expression of a variety of genes, thereby being an integral part of the genome-wide microRNA gene regulatory network.

Dataset Information

Ontogeny, conservation and functional significance of maternally inherited DNA methylation at two classes of non-imprinted genes.

Publications

Ontogeny, conservation and functional significance of maternally inherited DNA methylation at two classes of non-imprinted genes.

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