title: The histone variant MacroH2A1 regulates target gene expression in part by recruiting the transcriptional coregulator PELP1.
abstract: MacroH2A1 is a histone variant harboring an ∼25-kDa carboxyl-terminal macrodomain. Due to its enrichment on the inactive X chromosome, macroH2A1 was thought to play a role in transcriptional repression. However, recent studies have shown that macroH2A1 occupies autosomal chromatin and regulates genes in a context-specific manner. The macrodomain may play a role in the modulation of gene expression outcomes via physical interactions with effector proteins, which may depend on the ability of the macrodomain to bind NAD(+) metabolite ligands. Here, we identify proline, glutamic acid, and leucine-rich protein 1 (PELP1), a chromatin-associated factor and transcriptional coregulator, as a ligand-independent macrodomain-interacting factor. We used chromatin immunoprecipitation coupled with tiling microarrays (ChIP-chip) to determine the genomic localization of PELP1 in MCF-7 human breast cancer cells. We find that PELP1 genomic localization is highly correlated with that of macroH2A1. Additionally, PELP1 positively correlates with heterochromatic chromatin marks and negatively correlates with active transcription marks, much like macroH2A1. MacroH2A1 specifically recruits PELP1 to the promoters of macroH2A1 target genes, but macroH2A1 occupancy occurs independent of PELP1. This recruitment allows macroH2A1 and PELP1 to cooperatively regulate gene expression outcomes.
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York, USA.
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Hussey
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Hongshan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Park
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York, USA.
authors.forename: Nasun
authors.initials: N
authors.lastname: Hah
authors.affiliation: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.affiliation: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Tempst
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gamble
authors.affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York, USA Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, and Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas, USA matthew.gamble@einstein.yu.edu lee.kraus@utsouthwestern.edu.
authors.forename: W Lee
authors.initials: WL
authors.lastname: Kraus
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D056970:Co-Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D000900:Anti-Bacterial Agents; D002843:Chromatin; D056970:Co-Repressor Proteins; D006657:Histones; C438485:PELP1 protein, human; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D014157:Transcription Factors; C120756:macroH2A histone; D004318:Doxycycline
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