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.
Highlights
A role for CHD5 in cancer was first suggested by genetic mapping studies in neuroblastomas [1,2]
CHD5 mRNA is preferentially found in brain CHD5 expression was initially reported to be limited to brain, though others have found CHD5 expression elsewhere, so there is some controversy about sites of CHD5 expression [4,7,9,13,21]
We examined CHD5 mRNA in mouse and human organs, and found that CHD5 mRNA was abundant in brain, approximately 7 fold lower in mouse testes, and 2–4 orders of magnitude lower in all other tested mouse and human organs (Figure 1a,b)
Summary
A role for CHD5 in cancer was first suggested by genetic mapping studies in neuroblastomas [1,2]. All CHD members contain two N-terminal chromodomains, a helicase-like ATPase motif associated with nucleosome remodeling, and a less well-defined C-terminal DNA binding domain. The role of CHD5 in brain development and function remains to be determined. CHD3 and CHD4, known as Mi-2alpha and Mi-2ß, are found in multiprotein chromatin remodeling complexes named NuRD [23,24,25,26,27,28]. In addition to the ATPase activity of the CHD subunit, NuRD complexes include the histone deacetylases HDAC1 and HDAC2. Whether CHD5 exists in a multi-protein complex and functions to regulate gene expression in the brain has not been reported. Binding of CHD5 to some of these target genes in intact cells suggested they were directly regulated by CHD5
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