title: Interaction of the Jhd2 Histone H3 Lys-4 Demethylase with Chromatin Is Controlled by Histone H2A Surfaces and Restricted by H2B Ubiquitination.
abstract: Histone H3 lysine 4 (H3K4) methylation is a dynamic modification. In budding yeast, H3K4 methylation is catalyzed by the Set1-COMPASS methyltransferase complex and is removed by Jhd2, a JMJC domain family demethylase. The catalytic JmjC and JmjN domains of Jhd2 have the ability to remove all three degrees (mono-, di-, and tri-) of H3K4 methylation. Jhd2 also contains a plant homeodomain (PHD) finger required for its chromatin association and H3K4 demethylase functions. The Jhd2 PHD finger associates with chromatin independent of H3K4 methylation and the H3 N-terminal tail. Therefore, how Jhd2 associates with chromatin to perform H3K4 demethylation has remained unknown. We report a novel interaction between the Jhd2 PHD finger and histone H2A. Two residues in H2A (Phe-26 and Glu-57) serve as a binding site for Jhd2 in vitro and mediate its chromatin association and H3K4 demethylase functions in vivo. Using RNA sequencing, we have identified the functional target genes for Jhd2 and the H2A Phe-26 and Glu-57 residues. We demonstrate that H2A Phe-26 and Glu-57 residues control chromatin association and H3K4 demethylase functions of Jhd2 during positive or negative regulation of transcription at target genes. Importantly, we show that H2B Lys-123 ubiquitination blocks Jhd2 from accessing its binding site on chromatin, and thereby, we have uncovered a second mechanism by which H2B ubiquitination contributes to the trans-histone regulation of H3K4 methylation. Overall, our study provides novel insights into the chromatin binding dynamics and H3K4 demethylase functions of Jhd2.
authors.affiliation: the Stowers Institute for Medical Research, Kansas City, Missouri 64110, and.
authors.forename: Fu
authors.initials: F
authors.lastname: Huang
authors.affiliation: From the Departments of Radiation Oncology and the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Saravanan
authors.initials: S
authors.lastname: Ramakrishnan
authors.affiliation: From the Departments of Radiation Oncology and the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Srijana
authors.initials: S
authors.lastname: Pokhrel
authors.affiliation: the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Oncological Sciences and.
authors.forename: Christian
authors.initials: C
authors.lastname: Pflueger
authors.affiliation: the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Parnell
authors.affiliation: the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Oncological Sciences and.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Kasten
authors.affiliation: the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Oncological Sciences and.
authors.forename: Simon L
authors.initials: SL
authors.lastname: Currie
authors.affiliation: the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Oncological Sciences and.
authors.forename: Niraja
authors.initials: N
authors.lastname: Bhachech
authors.affiliation: the Laboratory of Developmental Biology, Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Horikoshi
authors.affiliation: the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Oncological Sciences and.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Graves
authors.affiliation: the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Oncological Sciences and.
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Cairns
authors.affiliation: From the Departments of Radiation Oncology and the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Oncological Sciences and.
authors.forename: Srividya
authors.initials: S
authors.lastname: Bhaskara
authors.affiliation: From the Departments of Radiation Oncology and the Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, mahesh.chandrasekharan@hci.utah.edu.
authors.forename: Mahesh B
authors.identifier: http://orcid.org/0000-0002-9956-8354
authors.initials: MB
authors.lastname: Chandrasekharan
mesh_terms: D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D002843:Chromatin; D006657:Histones; D029701:Saccharomyces cerevisiae Proteins; C519119:JHD2 protein, S cerevisiae; D056484:Jumonji Domain-Containing Histone Demethylases
keywords: H3K4 methylation; PHD finger; epigenetics; gene transcription; histone; histone demethylase; histone methylation; histone modification; nucleosome; protein-protein interaction; transcription