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

doi:10.1101/gad.270413.115

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

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

55 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 language	English (US)
Pages (from-to)	92-101
Number of pages	10
Journal	Genes and Development
Volume	30
Issue number	1
DOIs	https://doi.org/10.1101/gad.270413.115
State	Published - Jan 1 2016

Funding

We are grateful to Professor Didier Trono, Professor Stuart Orkin, Professor Colin Stewart, Professor Xiajun Li, and Professor Matthew Lorincz for providing cell lines for this study.We also thank the Molecular Biology core facility at the Stowers Institute for creating and sequencing libraries for next-generation sequencing, and the Stowers Tissue Culture facility for cell culture. We are also thankful to Laura Shilatifard for editorial assistance. Z.L. was supported as a Fellow of the Leukemia and Lymphoma Society. The study was supported in part by grant R01GM069905 from the National Institute of Health to A.S.

Keywords

Elongation control
Enhancers
Transcription

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Regulation of the imprinted Dlk1-Dio3 locus by allele-specific enhancer activity",

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.",

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AU - Smith, Edwin R.

AU - Shilatifard, Ali

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AB - 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.

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

Abstract

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Keywords

ASJC Scopus subject areas

UN SDGs

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