title: Human LSD2/KDM1b/AOF1 regulates gene transcription by modulating intragenic H3K4me2 methylation.
abstract: Dynamic histone H3K4 methylation is an important epigenetic component of transcriptional regulation. However, most of our current understanding of this histone mark is confined to the regulation of transcriptional initiation. We now show that human LSD2/KDM1b/AOF1, the human homolog of LSD1, is an H3K4me1/2 demethylase that specifically regulates histone H3K4 methylation within intragenic regions of its target genes. Genome-wide mapping reveals that LSD2 associates predominantly with the gene bodies of actively transcribed genes, but is markedly absent from promoters. Depletion of endogenous LSD2 results in an increase of H3K4me2 as well as a decrease of H3K9me2 at LSD2-binding sites and a consequent dysregulation of target gene transcription. Furthermore, characterization of the LSD2 complex reveals that LSD2 forms active complexes with euchromatic histone methyltransferases G9a and NSD3 as well as cellular factors involved in transcription elongation. These data provide a possible molecular mechanism linking LSD2 to transcriptional regulation after initiation.
authors.affiliation: Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Fang
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Barbera
authors.forename: Yufei
authors.initials: Y
authors.lastname: Xu
authors.forename: Michael
authors.initials: M
authors.lastname: Rutenberg
authors.forename: Thiago
authors.initials: T
authors.lastname: Leonor
authors.forename: Qing
authors.initials: Q
authors.lastname: Bi
authors.forename: Fei
authors.initials: F
authors.lastname: Lan
authors.forename: Pinchao
authors.initials: P
authors.lastname: Mei
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.forename: Christine
authors.initials: C
authors.lastname: Lian
authors.forename: Junmin
authors.initials: J
authors.lastname: Peng
authors.forename: Dongmei
authors.initials: D
authors.lastname: Cheng
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: Ursula B
authors.initials: UB
authors.lastname: Kaiser
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.forename: Yujiang Geno
authors.initials: YG
authors.lastname: Shi
mesh_terms: D001665:Binding Sites; D006367:HeLa Cells; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D006649:Histocompatibility Antigens; D006657:Histones; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D056466:Histone Demethylases; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; C432968:NSD3 protein, human