Les enzymes de remodelage de la chromatine dépendantes de l'ATP CHD6, CHD7 et CHD8 présentent des activités distinctes de liaison et de remodelage des nucléosomes

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