Regulation of the imprinted Dlk1-Dio3 locus by allele-specific enhancer activity

Zhuojuan Luo, Chengqi Lin, Ashley R. Woodfin*, Elizabeth T. Bartom, Xin Gao, Edwin R. Smith, Ali Shilatifard

*Corresponding author for this work

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Genomic imprinting is a critical developmental process characteristic of parent of origin-specific gene expression. It is well accepted that differentially DNA-methylated regions (DMRs) and enhancers are two major classes of ciselements determining parent of origin-specific gene expression, with each recruiting different sets of transcription factors. Previously, we identified the AF4/FMR2 (AFF) family protein AFF3 within the transcription elongation complex SEC-L3. Here, we report that AFF3 can specifically bind both gametic DMRs (gDMRs) and enhancers within imprinted loci in an allele-specific manner. We identify the molecular regulators involved in the recruitment of AFF3 to gDMRs and provide mechanistic insight into the requirement of AFF3 at an enhancer for the expression of an ∼200-kb polycistronic transcript within the imprinted Dlk1-Dio3 locus. Our data suggest that the heterochromatic environment at the gDMR reinforces silencing of its related enhancer by controlling the binding and activity of AFF3 in an allele-specific manner. In summary, this study provides molecular details about the regulation of dosage-critical imprinted gene expression through the regulated binding of the transcription elongation factor AFF3 between a DMR and an enhancer.

Original languageEnglish (US)
Pages (from-to)92-101
Number of pages10
JournalGenes and Development
Volume30
Issue number1
DOIs
StatePublished - Jan 1 2016

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Keywords

  • Elongation control
  • Enhancers
  • Transcription

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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