Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F18%3A00489776" target="_blank" >RIV/61388963:_____/18:00489776 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1038/s41594-017-0007-3" target="_blank" >http://dx.doi.org/10.1038/s41594-017-0007-3</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41594-017-0007-3" target="_blank" >10.1038/s41594-017-0007-3</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers

Popis výsledku v původním jazyce

Mutation of SMARCA4 (BRG1), the ATPase of BAF (mSWI/SNF) and PBAF complexes, contributes to a range of malignancies and neurologic disorders. Unfortunately, the effects of SMARCA4 missense mutations have remained uncertain. Here we show that SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical cycle of remodeling. We find that heterozygous expression of mutants alters the open chromatin landscape at thousands of sites across the genome. Loss of DNA accessibility does not directly overlap with Polycomb accumulation, but is enriched in 'A compartments' at active enhancers, which lose H3K27ac but not H3K4me1. Affected positions include hundreds of sites identified as superenhancers in many tissues. Dominant-negative mutation induces pro-oncogenic expression changes, including increased expression of Myc and its target genes. Together, our data suggest that disruption of enhancer accessibility represents a key source of altered function in disorders with SMARCA4 mutations in a wide variety of tissues.

Název v anglickém jazyce

Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers

Popis výsledku anglicky

Mutation of SMARCA4 (BRG1), the ATPase of BAF (mSWI/SNF) and PBAF complexes, contributes to a range of malignancies and neurologic disorders. Unfortunately, the effects of SMARCA4 missense mutations have remained uncertain. Here we show that SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical cycle of remodeling. We find that heterozygous expression of mutants alters the open chromatin landscape at thousands of sites across the genome. Loss of DNA accessibility does not directly overlap with Polycomb accumulation, but is enriched in 'A compartments' at active enhancers, which lose H3K27ac but not H3K4me1. Affected positions include hundreds of sites identified as superenhancers in many tissues. Dominant-negative mutation induces pro-oncogenic expression changes, including increased expression of Myc and its target genes. Together, our data suggest that disruption of enhancer accessibility represents a key source of altered function in disorders with SMARCA4 mutations in a wide variety of tissues.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/GA16-06357S" target="_blank" >GA16-06357S: Strukturní podstata biologické funkce LEDGF/p75 a HRP-2</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Nature structural & molecular biology

ISSN

1545-9993

e-ISSN

—

Svazek periodika

25

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

61-72

Kód UT WoS článku

000423547700010

EID výsledku v databázi Scopus

2-s2.0-85042743313