KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state.
Heterochromatin plays an essential role in the preservation of epigenetic information, the transcriptional repression of repetitive DNA elements and inactive genes, and the proper segregation of chromosomes during mitosis. Here we identify KDM2A, a JmjC-domain containing histone demethylase, as a heterochromatin-associated and HP1-interacting protein that promotes HP1 localization to chromatin. We show that KDM2A is required to maintain the heterochromatic state, as determined using a candidate-based approach coupled to an in vivo epigenetic reporter system. Remarkably, a parallel and independent siRNA screen also detected a role for KDM2A in epigenetic silencing. Moreover, we demonstrate that KDM2A associates with centromeres and represses transcription of small non-coding RNAs that are encoded by the clusters of satellite repeats at the centromere. Dissecting the relationship between heterochromatin and centromeric RNA transcription is the basis of ongoing studies. We demonstrate that forced expression of these satellite RNA transcripts compromise the heterochromatic state and HP1 localization to chromatin. Finally, we show that KDM2A is required to sustain centromeric integrity and genomic stability, particularly during mitosis. Since the disruption of epigenetic control mechanisms contributes to cellular transformation, these results, together with the low levels of KDM2A found in prostate carcinomas, suggest a role for KDM2A in cancer development.
Frescas
David
D
Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.
Guardavaccaro
Daniele
D
Kuchay
Shafi M
SM
Kato
Hiroyuki
H
Poleshko
Andrey
A
Basrur
Venkatesha
V
Elenitoba-Johnson
Kojo S
KS
Katz
Richard A
RA
Pagano
Michele
M
D016475:3T3 Cells; D000818:Animals; D002471:Cell Transformation, Neoplastic; D002503:Centromere / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004276:DNA, Satellite / Q000235:genetics*; D044783:F-Box Proteins; D042822:Genomic Instability; D006367:HeLa Cells; D006570:Heterochromatin / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D051379:Mice; D010089:Oxidoreductases, N-Demethylating / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
D004276:DNA, Satellite; D044783:F-Box Proteins; D006570:Heterochromatin; D006657:Histones; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; D010089:Oxidoreductases, N-Demethylating