The ATP-dependent chromatin remodeling enzymes CHD6, CHD7, and CHD8 exhibit distinct nucleosome binding and remodeling activities.

Abstract

Proper chromatin regulation is central to genome function and maintenance. The group III chromodomain-helicase-DNA-binding (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, but they 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, whereas CHD8 requires longer DNA for binding. As a result, CHD8 slides nucleosomes into positions with more flanking linker DNA than CHD7. Moreover, we found that, although 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.

• Authors: Benjamin J Manning, Timur Yusufzai
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 28 Pg. 11927-11936 (07 14 2017) ISSN: 1083-351X [Electronic] United States
• PMID: 28533432 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• CHD6 protein, human
• CHD8 protein, human
• DNA, Recombinant
• DNA, Viral
• DNA-Binding Proteins
• Nerve Tissue Proteins
• Nucleosomes
• Recombinant Proteins
• Transcription Factors
• Adenosine Triphosphate
• DNA
• DNA Helicases
• CHD7 protein, human

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Biological Transport
• Chromatin Assembly and Disassembly
• DNA (chemistry, metabolism)
• DNA Helicases (chemistry, genetics, isolation & purification, metabolism)
• DNA, Recombinant (chemistry, metabolism)
• DNA, Viral (chemistry, metabolism)
• DNA-Binding Proteins (chemistry, genetics, isolation & purification, metabolism)
• HeLa Cells
• Humans
• Hydrolysis
• Kinetics
• Molecular Weight
• Nerve Tissue Proteins (chemistry, genetics, isolation & purification, metabolism)
• Nucleosomes (enzymology, metabolism)
• Phylogeny
• Recombinant Proteins (chemistry, isolation & purification, metabolism)
• Sf9 Cells
• Spodoptera
• Transcription Factors (chemistry, genetics, isolation & purification, metabolism)