Aperçu: G.M.
Une bonne régulation de la chromatine est essentielle à la fonction et à la maintenance du génome. La
famille de CHD du groupe III d'enzymes de remodelage de la chromatine
dépendantes de l'ATP - comprenant CHD6, CHD7, CHD8 et CHD9 - a des rôles
bien documentés dans la régulation de la transcription qui ont un
impact sur le développement de l'organisme et l'étiologie de la maladie.
Ces
quatre enzymes sont similaires dans leurs domaines constitutifs, mais
ces enzymes remplissent des rôles étonnamment non redondants dans la
cellule, avec des déficiences dans les enzymes individuelles conduisant à
des états de maladie dissemblables tels que le syndrome de CHARGE ou
les troubles du spectre de l'autisme.
Dans l'ensemble, le travail des chercheurs fournit une base mécanique pour les
rôles non redondants et les divers états pathologiques mutants, de ces
enzymes in vivo.
J Biol Chem. 2017 May 21. pii: jbc.M117.779470. doi: 10.1074/jbc.M117.779470.
The ATP-dependent Chromatin Remodeling Enzymes CHD6, CHD7, and CHD8 Exhibit Distinct Nucleosome Binding and Remodeling Activities
Manning BJ1, Yusfuzai T2.
Author information
- 1
- Dana-Farber Cancer Institute, United States.
- 2
- Dana-Farber Cancer Institute, United States timur_yusufzai@dfci.harvard.edu
Abstract
Proper
chromatin regulation is central to genome function and maintenance. The
group III CHD family of ATP-dependent chromatin remodeling
enzymes--comprising CHD6, CHD7, CHD8, and CHD9--has well-documented
roles in transcription regulation impacting both organism development
and disease etiology. These four enzymes are similar in their
constituent domains, yet these enzymes fill surprisingly non-redundant
roles in the cell, with deficiencies in individual enzymes leading to
dissimilar disease states such as CHARGE syndrome or autism
spectrum disorders. The mechanisms explaining their divergent,
non-overlapping functions are unclear. In this study, we performed an
in-depth biochemical analysis of purified CHD6, CHD7, and CHD8, and
discovered distinct differences in chromatin remodeling specificities
and activities among them. We report that CHD6 and CHD7 both bind with
high affinity to short linker DNA, while CHD8 requires longer DNA for
binding. As a result, CHD8 slides nucleosomes into positions with more
flanking linker DNA than does CHD7. Moreover, we found that while CHD7
and CHD8 slide nucleosomes, CHD6 disrupts nucleosomes in a distinct
non-sliding manner. The different activities of these enzymes likely
lead to differences in chromatin structure, and thereby transcriptional
control, at the enhancer and promoter loci where these enzymes bind.
Overall, our work provides a mechanistic basis for both the
non-redundant roles, and the diverse mutant disease states, of these
enzymes in vivo.
Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
- PMID: 28533432
- DOI: 10.1074/jbc.M117.779470
