CHD5, a Brain-Specific Paralog of Mi2 Chromatin Remodeling Enzymes, Regulates Expression of Neuronal Genes

Abstract

CHD5 is frequently deleted in neuroblastoma and is a tumor suppressor gene. However, little is known about the role of CHD5 other than it is homologous to chromatin remodeling ATPases. We found CHD5 mRNA was restricted to the brain; by contrast, most remodeling ATPases were broadly expressed. CHD5 protein isolated from mouse brain was associated with HDAC2, p66ß, MTA3 and RbAp46 in a megadalton complex. CHD5 protein was detected in several rat brain regions and appeared to be enriched in neurons. CHD5 protein was predominantly nuclear in primary rat neurons and brain sections. Microarray analysis revealed genes that were upregulated and downregulated when CHD5 was depleted from primary neurons. CHD5 depletion altered expression of neuronal genes, transcription factors, and brain-specific subunits of the SWI/SNF remodeling enzyme. Expression of gene sets linked to aging and Alzheimer's disease were strongly altered by CHD5 depletion from primary neurons. Chromatin immunoprecipitation revealed CHD5 bound to these genes, suggesting the regulation was direct. Together, these results indicate that CHD5 protein is found in a NuRD-like multi-protein complex. CHD5 expression is restricted to the brain, unlike the closely related family members CHD3 and CHD4. CHD5 regulates expression of neuronal genes, cell cycle genes and remodeling genes. CHD5 is linked to regulation of genes implicated in aging and Alzheimer's disease.

Histone Regulation in the CNS: Basic Principles of Epigenetic Plasticity

“…In trisomy 21, however, DYRK1A is dysregulated, thereby leading to increased expression of NRSF/REST, subsequent disturbances in NRSF/REST-SWI/SNF complex assembly, and deficits in dendritic growth/complexity in the adult brain. Taken together, these data, along with findings demonstrating the existence of brain-specific/-restricted chromatinremodeling proteins (eg, CHD5, a remodeling ATPase known to interact with HDAC2, which has been linked to gene expression patterns associated with aging and Alzheimer's disease) (Potts et al, 2011), demonstrate that regulatory control over chromatin-remodeling activities/ enzymes in the adult CNS is important to numerous aspects of adult neurological function; however, dissecting the developmental vs adulthood contributions of such complexes to neuropsychiatric disease remains difficult.…”

1p36 Tumor Suppression—A Matter of Dosage?

“…Another interaction level may be convergence of signals downstream of 1p36 genes on identical pathways. In an adequate cellular context, CHD5, CAMTA1, CASZ1, and miR-34a all activate genetic programs implicated in neuronal function and differentiation (31,55,75,120). Expression of neuronspecific gene sets is associated with a markedly better prognosis in both neuroblastomas and gliomas (68,121,122).…”

“…CHD5 resides in 1p36.31, is preferentially expressed in neuronal tissues, and its product regulates genes involved in neuronal function, cell-cycle control, and chromatin remodeling (31). Functional evidence for a tumor suppressive role of mouse Chd5 derives from an elegant approach using chromosome engineering to generate mouse models with loss or gain of genomic regions corresponding to human 1p36 (22).…”

Tagging Methyl-CpG-Binding Domain Proteins Reveals Different Spatiotemporal Expression and Supports Distinct Functions

“…Alternatively, MBD3/NuRD may be the principal form of NuRD in the brain, as it is expressed in this tissue (Figure 8) and other studies have shown that it affects synaptic connectivity in addition to regulating cortical neuronal differentiation [33,34]. A related explanation for absence of significant MBD2-dependent brain function is that a brain-specific, alternate form of NuRD that interacts with MBD3, but not MBD2, may be acting predominantly in the brain in vivo [36].…”

“…Mbd1 knockout mice also exhibit behavioral phenotypes that mimic features of ASD such as learning and memory deficits, reduced sociability, and changes in anxiety-related phenotypes [22,29]. Furthermore, MBD3 and multiple components of the MBD-associated corepressor complexes, such as NuRD, Sin3A and NCoR/SMRT, also have critical roles in the brain [33][34][35][36][37]. Given the similarities between the MBD proteins, it has been postulated that MBD2 may also have a role in brain function [6].…”