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 cis-elements 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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA; Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;
authors.forename: Zhuojuan
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;
authors.forename: Chengqi
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Woodfin
authors.affiliation: Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Bartom
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA;
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Smith
authors.affiliation: Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA; Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA; Robert H. Lurie National Cancer Institute Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Shilatifard
mesh_terms: D000483:Alleles; D000818:Animals; D002135:Calcium-Binding Proteins; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D053595:Embryonic Stem Cells; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D020868:Gene Silencing; D018392:Genomic Imprinting / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D007453:Iodide Peroxidase / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C422882:MEG3 non-coding RNA, mouse; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase
keywords: elongation control; enhancers; transcription