Molecular Interplay of the Noncoding RNA ANRIL and Methylated Histone H3 Lysine 27 by Polycomb CBX7 in Transcriptional Silencing of INK4a

Kyoko L. Yap; Side Li; Ana M. Muñoz-Cabello; Selina Raguz; Lei Zeng; Shiraz Mujtaba; Jesús Gil; Martin J. Walsh; Ming Ming Zhou

doi:10.1016/j.molcel.2010.03.021

Molecular Interplay of the Noncoding RNA ANRIL and Methylated Histone H3 Lysine 27 by Polycomb CBX7 in Transcriptional Silencing of INK4a

Kyoko L. Yap, Side Li, Ana M. Muñoz-Cabello, Selina Raguz, Lei Zeng, Shiraz Mujtaba, Jesús Gil, Martin J. Walsh, Ming Ming Zhou

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Abstract

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.

Original language	English
Pages (from-to)	662-674
Number of pages	13
Journal	Molecular Cell
Volume	38
Issue number	5
DOIs	https://doi.org/10.1016/j.molcel.2010.03.021
State	Published - 11 Jun 2010

Keywords

DNA
PROTEINS

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@article{c03c8efb658c41cea247a37e0fc4713c,

title = "Molecular Interplay of the Noncoding RNA ANRIL and Methylated Histone H3 Lysine 27 by Polycomb CBX7 in Transcriptional Silencing of INK4a",

abstract = "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.",

keywords = "DNA, PROTEINS",

author = "Yap, {Kyoko L.} and Side Li and Mu{\~n}oz-Cabello, {Ana M.} and Selina Raguz and Lei Zeng and Shiraz Mujtaba and Jes{\'u}s Gil and Walsh, {Martin J.} and Zhou, {Ming Ming}",

note = "Funding Information: We wish to acknowledge the use of the NMR Facility at the New York Structural Biology Center. We thank S. Hearn of the Cold Spring Harbor Laboratory Core Microscopy Facility for advice and help with fluorescence microscopy and imaging, G. Gerona-Navarro for fluorescein-labeled peptide, and A. Kelly for help with data analysis. This work was supported by a Terry Fox Foundation postdoctoral fellowship from the National Cancer Institute of Canada (K.L.Y.) and by grants from the Empire State Stem Cell Trust Fund (NYSTEM) and the National Institutes of Health (M.-M.Z. and M.J.W.), Medical Research Council (MRC) UK (J.G.), and the National Science Foundation (M.-M.Z.). ",

year = "2010",

month = jun,

day = "11",

doi = "10.1016/j.molcel.2010.03.021",

language = "English",

volume = "38",

pages = "662--674",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

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T1 - Molecular Interplay of the Noncoding RNA ANRIL and Methylated Histone H3 Lysine 27 by Polycomb CBX7 in Transcriptional Silencing of INK4a

AU - Yap, Kyoko L.

AU - Li, Side

AU - Muñoz-Cabello, Ana M.

AU - Raguz, Selina

AU - Zeng, Lei

AU - Mujtaba, Shiraz

AU - Gil, Jesús

AU - Walsh, Martin J.

AU - Zhou, Ming Ming

N1 - Funding Information: We wish to acknowledge the use of the NMR Facility at the New York Structural Biology Center. We thank S. Hearn of the Cold Spring Harbor Laboratory Core Microscopy Facility for advice and help with fluorescence microscopy and imaging, G. Gerona-Navarro for fluorescein-labeled peptide, and A. Kelly for help with data analysis. This work was supported by a Terry Fox Foundation postdoctoral fellowship from the National Cancer Institute of Canada (K.L.Y.) and by grants from the Empire State Stem Cell Trust Fund (NYSTEM) and the National Institutes of Health (M.-M.Z. and M.J.W.), Medical Research Council (MRC) UK (J.G.), and the National Science Foundation (M.-M.Z.).

PY - 2010/6/11

Y1 - 2010/6/11

N2 - 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.

AB - 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.

KW - DNA

KW - PROTEINS

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U2 - 10.1016/j.molcel.2010.03.021

DO - 10.1016/j.molcel.2010.03.021

M3 - Article

C2 - 20541999

AN - SCOPUS:77953096072

SN - 1097-2765

VL - 38

SP - 662

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JO - Molecular Cell

JF - Molecular Cell

IS - 5

ER -

Molecular Interplay of the Noncoding RNA ANRIL and Methylated Histone H3 Lysine 27 by Polycomb CBX7 in Transcriptional Silencing of INK4a

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