Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a.
Expression of the INK4b/ARF/INK4a tumor suppressor locus in normal and cancerous cell growth is controlled by methylation of histone H3 at lysine 27 (H3K27me) as directed by the Polycomb group proteins. The antisense noncoding RNA ANRIL of the INK4b/ARF/INK4a locus is also important for expression of the protein-coding genes in cis, but its mechanism has remained elusive. Here we report that chromobox 7 (CBX7) within the polycomb repressive complex 1 binds to ANRIL, and both CBX7 and ANRIL are found at elevated levels in prostate cancer tissues. In concert with H3K27me recognition, binding to RNA contributes to CBX7 function, and disruption of either interaction impacts the ability of CBX7 to repress the INK4b/ARF/INK4a locus and control senescence. Structure-guided analysis reveals the molecular interplay between noncoding RNA and H3K27me as mediated by the conserved chromodomain. Our study suggests a mechanism by which noncoding RNA participates directly in epigenetic transcriptional repression.
Yap
Kyoko L
KL
Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Li
Side
S
Muñoz-Cabello
Ana M
AM
Raguz
Selina
S
Zeng
Lei
L
Mujtaba
Shiraz
S
Gil
Jesús
J
Walsh
Martin J
MJ
Zhou
Ming-Ming
MM
D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008297:Male; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D019906:Nuclear Magnetic Resonance, Biomolecular; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
C503627:CBX7 protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D063146:Polycomb-Group Proteins; D022661:RNA, Untranslated; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D008239:Lysine