A Functional Switch of NuRD Chromatin Remodeling Complex Subunits Regulates Mouse Cortical Development

Justyna Nitarska,Jacob G Smith,William T Sherlock,Michele M.G Hillege,Alexi Nott,William D Barshop,Ajay A Vashisht,James A Wohlschlegel,Richard Mitter,Antonella Riccio

doi:10.1016/j.celrep.2016.10.022

Abstract

SummaryHistone modifications and chromatin remodeling represent universal mechanisms by which cells adapt their transcriptional response to rapidly changing environmental conditions. Extensive chromatin remodeling takes place during neuronal development, allowing the transition of pluripotent cells into differentiated neurons. Here, we report that the NuRD complex, which couples ATP-dependent chromatin remodeling with histone deacetylase activity, regulates mouse brain development. Subunit exchange of CHDs, the core ATPase subunits of the NuRD complex, is required for distinct aspects of cortical development. Whereas CHD4 promotes the early proliferation of progenitors, CHD5 facilitates neuronal migration and CHD3 ensures proper layer specification. Inhibition of each CHD leads to defects of neuronal differentiation and migration, which cannot be rescued by expressing heterologous CHDs. Finally, we demonstrate that NuRD complexes containing specific CHDs are recruited to regulatory elements and modulate the expression of genes essential for brain development.

Highlights

The ability to adjust the transcriptional output in response to ever-changing environmental conditions lies at the core of organismal development
Cortices were dissected at embryonic day 12.5 (E12.5), E15.5, and E18.5, and cell lysates were incubated with HDAC2 antibody or normal immunoglobulin G (IgG)
HDAC2 co-immunoprecipitation followed by western blot analysis of CHD3, CHD4, CHD5, MTA1, MTA2, and Rbbp7 confirmed the findings of mass spectrometry analysis and revealed that the association of chromodomain-helicase DNA-binding proteins (CHDs) with HDAC2 changed according to developmental stage (Figures 1A and 1B)

Summary

Introduction

The ability to adjust the transcriptional output in response to ever-changing environmental conditions lies at the core of organismal development. Epigenetic modifications and changes of chromatin structure are emerging as fundamental mechanisms that regulate gene expression during brain development (Hirabayashi and Gotoh, 2010; Riccio, 2010). Chromatin is a highly dynamic structure that can be modified by a number of mechanisms, including DNA methylation, histone post-translational modifications, and ATP-dependent remodeling of chromatin (Borrelli et al, 2008). The latter mechanism uses energy released by hydrolysis of ATP to induce nucleosome sliding, facilitating the recruitment of transcriptional complexes (Narlikar et al, 2013) that activate or inhibit gene expression

Results

Discussion

Conclusion