Human LSD2/KDM1b/AOF1 regulates gene transcription by modulating intragenic H3K4me2 methylation.
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.
Fang
Rui
R
Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, USA.
Barbera
Andrew J
AJ
Xu
Yufei
Y
Rutenberg
Michael
M
Leonor
Thiago
T
Bi
Qing
Q
Lan
Fei
F
Mei
Pinchao
P
Yuan
Guo-Cheng
GC
Lian
Christine
C
Peng
Junmin
J
Cheng
Dongmei
D
Sui
Guangchao
G
Kaiser
Ursula B
UB
Shi
Yang
Y
Shi
Yujiang Geno
YG
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*
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