Role of DNA methylation in transcriptional regulation
Perricone, Sara Maria
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In mammals, the correct spatio-temporal patterns of gene expression are coordinated by transcription factor networks in combination with epigenetic signalling pathways. CpG methylation is an epigenetic modification of DNA involved in the heritable transmission of gene silencing patterns. Increasing evidence suggest a primary role for CpG methylation in the direct regulation of gene expression, at least for a subset of promoters. An example of this direct regulation is represented by the ectopic expression of genes involved in genome defence pathways upon global loss of methylation. However, the mechanistic relationship between CpG methylation and transcriptional regulation is not well understood. To explore this, we have applied Cap Analysis of Gene Expression (CAGE), to cells deficient in CpG methylation (Mouse Embryonic Fibroblasts with hypomorphic mutation of Dnmt1 ) and matched controls. This provides a quantitative, single nucleotide resolution, genome wide map of methylation responsive transcription initiation. Integrating this with RNA-seq, genome wide measures of CpG methylation and ChIP-seq for histone modifications in the same system, provides a detailed view of how reduced CpG methylation alters the chromatin and transcriptional landscape of the genome. Our results show dramatic shifts in the cellular RNA pool, with the pronounced up-regulation or de-repression of promoters in a specific sub-family of transposable elements. Tens of other genic and non-coding RNA promoters similarly show dramatic inductions. Contrary to a prior hypothesis, we found no evidence for increased rates of transcriptional initiation from anonymous genomic sites not previously implicated in promoter activity. Transcription initiation at CpG island promoters is generally unaffected by hypomethylation, however a set of TSSs located in CpG island shores and a class to transposable element overlapping TSSs do appear to be sensitive to methylation and are significantly up-regulated upon hypomethylation.