Publication Date:
2013-03-30
Description:
Sequencing of pediatric gliomas has identified missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding histone H3.3 (H3F3A) and H3.1 (HIST3H1B). We report that human diffuse intrinsic pontine gliomas (DIPGs) containing the K27M mutation display significantly lower overall amounts of H3 with trimethylated lysine 27 (H3K27me3) and that histone H3K27M transgenes are sufficient to reduce the amounts of H3K27me3 in vitro and in vivo. We find that H3K27M inhibits the enzymatic activity of the Polycomb repressive complex 2 through interaction with the EZH2 subunit. In addition, transgenes containing lysine-to-methionine substitutions at other known methylated lysines (H3K9 and H3K36) are sufficient to cause specific reduction in methylation through inhibition of SET-domain enzymes. We propose that K-to-M substitutions may represent a mechanism to alter epigenetic states in a variety of pathologies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951439/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951439/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lewis, Peter W -- Muller, Manuel M -- Koletsky, Matthew S -- Cordero, Francisco -- Lin, Shu -- Banaszynski, Laura A -- Garcia, Benjamin A -- Muir, Tom W -- Becher, Oren J -- Allis, C David -- DP2OD007447/OD/NIH HHS/ -- GM040922/GM/NIGMS NIH HHS/ -- R01 GM040922/GM/NIGMS NIH HHS/ -- R01 GM107047/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 May 17;340(6134):857-61. doi: 10.1126/science.1232245. Epub 2013 Mar 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23539183" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Substitution
;
Animals
;
Brain Neoplasms/*enzymology/*genetics
;
Child
;
*Epigenesis, Genetic
;
Glioblastoma/*enzymology/*genetics
;
HEK293 Cells
;
Histones/*genetics/metabolism
;
Humans
;
Lysine/genetics
;
Methionine/genetics
;
Methylation
;
Mice
;
Mutation, Missense
;
Polycomb Repressive Complex 2/*antagonists & inhibitors/metabolism
;
Transgenes
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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