ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression
Xiaobing Shi,Tao Hong,Kay L. Walter,Mark D. Ewalt,Eriko Michishita,Tiffany Hung,Dylan Carney,Pedro V. Peña,Fei Lan,Mohan R. Kaadige,Nicolas Lacoste,Christelle Cayrou,Foteini Davrazou,Anjanabha Saha,Bradley R. Cairns,Donald E. Ayer,Tatiana G. Kutateladze,Yang Shi,Jacques Côté,Katrin F. Chua,Katrin F. Chua,Or Gozani +21 more
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TLDR
A novel class of methylated H3K4 effector domains—the PHD domains of the ING (for inhibitor of growth) family of tumour suppressor proteins—are identified and established a pivotal role for trimethylation of H 3K4 in gene repression and, potentially, tumour suppressing mechanisms.Abstract:
Dynamic regulation of diverse nuclear processes is intimately linked to covalent modifications of chromatin. Much attention has focused on methylation at lysine 4 of histone H3 (H3K4), owing to its association with euchromatic genomic regions. H3K4 can be mono-, di- or tri-methylated. Trimethylated H3K4 (H3K4me3) is preferentially detected at active genes, and is proposed to promote gene expression through recognition by transcription-activating effector molecules. Here we identify a novel class of methylated H3K4 effector domains--the PHD domains of the ING (for inhibitor of growth) family of tumour suppressor proteins. The ING PHD domains are specific and highly robust binding modules for H3K4me3 and H3K4me2. ING2, a native subunit of a repressive mSin3a-HDAC1 histone deacetylase complex, binds with high affinity to the trimethylated species. In response to DNA damage, recognition of H3K4me3 by the ING2 PHD domain stabilizes the mSin3a-HDAC1 complex at the promoters of proliferation genes. This pathway constitutes a new mechanism by which H3K4me3 functions in active gene repression. Furthermore, ING2 modulates cellular responses to genotoxic insults, and these functions are critically dependent on ING2 interaction with H3K4me3. Together, our findings establish a pivotal role for trimethylation of H3K4 in gene repression and, potentially, tumour suppressor mechanisms.read more
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References
More filters
Journal ArticleDOI
Translating the Histone Code
Thomas Jenuwein,C. David Allis +1 more
TL;DR: It is proposed that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
PatentDOI
Histone demethylation mediated by the nuclear amine oxidase homolog lsd1
Yang Shi,Yujiang Shi +1 more
TL;DR: In this paper, the authors identify a histone demethylase conserved from S. pombe to human and reveal dynamic regulation of histone methylation by both histonemethylases and demethylases.
Journal ArticleDOI
Genomic Maps and Comparative Analysis of Histone Modifications in Human and Mouse
Bradley E. Bernstein,Bradley E. Bernstein,Bradley E. Bernstein,Michael Kamal,Kerstin Lindblad-Toh,Stefan Bekiranov,Dione K. Bailey,Dana J. Huebert,Dana J. Huebert,Scott McMahon,Scott McMahon,Elinor K. Karlsson,Edward J. Kulbokas,Thomas R. Gingeras,Stuart L. Schreiber,Stuart L. Schreiber,Eric S. Lander,Eric S. Lander +17 more
TL;DR: Methylation patterns at orthologous loci are strongly conserved between human and mouse even though many methylated sites do not show sequence conservation notably higher than background, which suggests that the DNA elements that direct the methylation represent only a small fraction of the region or lie at some distance from the site.
Journal ArticleDOI
Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6
Raul Mostoslavsky,Katrin F. Chua,Katrin F. Chua,David B. Lombard,Wendy W. Pang,Miriam R. Fischer,Lionel Gellon,Pingfang Liu,Gustavo Mostoslavsky,Sonia Franco,Michael M. Murphy,Kevin D. Mills,Parin Patel,Joyce T. Hsu,Andrew L. Hong,Ethan Ford,Hwei Ling Cheng,Caitlin Kennedy,Nomeli P. Nunez,Nomeli P. Nunez,Roderick T. Bronson,David Frendewey,Wojtek Auerbach,David M. Valenzuela,Margaret Karow,Michael O. Hottiger,Stephen D. Hursting,J. Carl Barrett,J. Carl Barrett,Leonard Guarente,Richard C. Mulligan,Bruce Demple,George D. Yancopoulos,Frederick W. Alt +33 more
TL;DR: It is demonstrated that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER).
Journal ArticleDOI
A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling
Joanna Wysocka,Tomek Swigut,Hua Xiao,Thomas A. Milne,So Yeon Kwon,Joseph Landry,Monika Kauer,Alan J. Tackett,Brian T. Chait,Paul Badenhorst,Carl Wu,C. David Allis +11 more
TL;DR: This work shows that a plant homeodomain (PHD) finger of nucleosome remodelling factor (NURF), an ISWI-containing ATP-dependent chromatin-remodelling complex, mediates a direct preferential association with H3K4me3 tails, and identifies a previously unknown function for the PHD finger as a highly specialized methyl-lysine-binding domain.