CHD7 promotes neural progenitor differentiation in embryonic stem cells via altered chromatin accessibility and nascent gene expression

Abstract

CHARGE syndrome, a rare multiple congenital anomaly condition, is caused by haploinsufficiency of the chromatin remodeling protein gene CHD7 (Chromodomain helicase DNA binding protein 7). Brain abnormalities and intellectual disability are commonly observed in individuals with CHARGE, and neuronal differentiation is reduced in CHARGE patient-derived iPSCs and conditional knockout mouse brains. However, the mechanisms of CHD7 function in nervous system development are not well understood. In this study, we asked whether CHD7 promotes gene transcription in neural progenitor cells via changes in chromatin accessibility. We used Chd7 null embryonic stem cells (ESCs) derived from Chd7 mutant mouse blastocysts as a tool to investigate roles of CHD7 in neuronal and glial differentiation. Loss of Chd7 significantly reduced neuronal and glial differentiation. Sholl analysis showed that loss of Chd7 impaired neuronal complexity and neurite length in differentiated neurons. Genome-wide studies demonstrated that loss of Chd7 leads to modified chromatin accessibility (ATAC-seq) and differential nascent expression (Bru-Seq) of neural-specific genes. These results suggest that CHD7 acts preferentially to alter chromatin accessibility of key genes during the transition of NPCs to neurons to promote differentiation. Our results form a basis for understanding the cell stage-specific roles for CHD7-mediated chromatin remodeling during cell lineage acquisition.

Hybrid schwannoma–perineurioma frequently harbors VGLL3 rearrangement

“…These proteins appear to be involved in transcription regulation, via chromatin remodeling, and rRNA biogenesis ( 28 ). CHD7 promotes neural crest formation( 29 ) and neural progenitor differentiation ( 30 ), amongst other diverse associations. Germline mutations in CHD7 are associated with CHARGE syndrome – Coloboma, Heart disease, Atresia choanae, Retarded growth and retarded development and/or CNS anomalies, Genital hypoplasia, and Ear anomalies and/or deafness – which is considered by some a neurocristopathy ( 29 , 31 , 32 ).…”

CHD8 safeguards early neuroectoderm differentiation in human ESCs and protects from apoptosis during neurogenesis

“…In fact, several CHD family members have been reported to participate in neurogenesis and the related mutations in these CHD members are correlated with neurodevelopmental disorders [ 6 ]. CHD2 knockout causes impaired cortical interneuron differentiation from human ESCs or failure of the neural differentiation from mouse ESCs, while Chd2 knockdown in E13.5 mouse cortices mediated by siRNA leads to reduced proliferation and premature differentiation of the progenitor cells [ 3 , 42 , 43 ]; CHD3, CHD4 and CHD5, as a component of nucleosome remodeling and deacetylase (NuRD) complex, are required for proliferation and migration of neuron in cortical development shown by mouse knockdown experiments [ 44 , 45 ]; human ESCs with CHD7 knockdown fail to differentiate into neural crest-like cells, and loss of Chd7 in mouse ESCs impaired the neuronal lineage differentiation [ 46 , 47 ]. Additionally, CHD1 knockout in mouse and human ESC models leads to a high propensity for neuronal differentiation at the expense of mesendoderm differentiation [ 38 , 41 ].…”

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

“…Similarly, mESCs from Chd7 Gt/Gt mice showed a reduced potential to differentiate into neuronal and glial lineages, and presented with altered accessibility and expression of NPC genes. Furthermore, neurons generated from these Chd7 Gt/Gt mESCs presented with a significant lower length and complexity [ 225 ]. Furthermore, CHD7 plays a key role in oligodendrocyte precursor survival and differentiation (Fig.…”