Proximal and Distal Regulation

[PMID:28343628] [American Journal of Human Genetics]

Functional Architectures of Local and Distal Regulation of Gene Expression in Multiple Human Tissues

“Analyses of the genetic correlation of gene expression across tissues confirmed that local regulation of gene expression is largely shared across tissues but that distal regulation is highly tissue specific. Work from Alkes Price.

[PMID:28223400] [Genome Research]

Distal CpG islands can serve as alternative promoters to transcribe genes with silenced proximal promoters

“through extensive analysis of the methylome and transcriptome in 34 tissues, that in many such cases, transcription is initiated by a distal upstream CpG island (CGI) located several kilobases away that functions as an alternative promoter.” “While the link between CGIs and downstream gene expression can be construed as a mode of distal enhancer-mediated regulation instead of alternative promoter action, we did not find any support to sustain that notion.” “A recent study that derived CGI annotations from experimental methylation data (eCGIs) also showed that promoter-distal eCGIs exhibited the most tissue-specific methylation patterns and were linked to the tissue-specific production of alternative transcripts” “a hitherto unreported conserved mechanism of transcription of genes with methylated proximal promoters in a tissue-specific fashion. Importantly, this phenomenon explains the aberrant expression patterns of some cancer driver genes, potentially due to aberrant hypomethylation of distal CGIs, despite methylation at proximal promoters.”

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