Progress: 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 brain;by contrast most remodeling ATPases were broadly expressed. CHD5 protein isolated from mouse brain was associated with HDAC2, p66, MTA3, MBD3 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 Alzheimers disease were strongly altered by CHD5 depletion from primary neurons;CHD5 was required for expression of genes that were upregulated in aging and Alzheimers', and CHD5 was required for repression of genes that were downregulated during aging and Alzheimers'. Specific Alzheimers'and aging targets, such as APP and APOE, were also regulated by CHD5. CHD5 regulated the neuron-specific SWI/SNF chromatin remodeling enzyme nBAF subunits BAF45a and BAF53a. CHD5 regulated genes involved in synapse formation and plasticity, such as BAF45a, Nrxn1 and Fmr1, and GO terms including Synapse organization and biogenesis, postsynaptic membrane, neuron projection, forebrain development, and dendrite, and the pathway Rett_DN.. 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, Alzheimers disease, and Rett Syndrome. This work was published in PLoS ONE (PMID: 21931736;PMCID: PMC3172237). Gene expression primary data were deposited in GEO (GSE27620), and are publicly available. This work may provide new insight into Alzheimers and Alzheimers pathways, as the CHD5 chromatin remodeling enzyme regulates genes previously identified as misregulated in the brains of human Alzheimers'patients. This work may provide new insight into aging and aging pathways, as the CHD5 chromatin remodeling enzyme regulates genes previously identified as displaying age-dependant regulation in the brains of humans. This work may provide new insights into neuroblastoma, as CHD5 is known to be a tumor suppressor for neuroblastoma;however, little was known about the function of CHD5 in neurons. CHD5 has also been suggested to be a tumor suppressor for other cancers;again, little is known about the function of CHD5, so this work may provide new information about other cancers as well. This work may provide new insight into synaptic plasticity, and disorders involving synaptic plasticity (such as autism spectrum disorders). Past epidemiological studies have not identified CHD5 mutations as a cause of ASD. However, we find CHD5 regulates ASD genes (FMR1, NRXN1, Rett pathway), and as a brain-specific molecule, it is a potential therapeutic target. Recent research by others supports these connections. Hydroxymethylcytosine (5hmC) has been found by others in the brain (Nucleic Acids Res. 2011, 39:5015, PMID: 21378125). 5hmC is depleted in cancer (PLoS One. 2012, 7:e41036, PMID: 22829908;Cancer Res. 2011, 71:7360, PMID: 22052461). 5hmC is elevated during aging and by Alzheimers (Curr Alzheimer Res. 2012, 9(5):545, PMID: 22272626;Curr Alzheimer Res. 2012, 9:536, PMID: 22272625;Nat Neurosci. 2011, 14:1607, PMID: 22037496). MBD3 has been found to interact with 5hmC (Cell. 2011, 147:1498, PMID: 22196727). 5hmC is inversely correlated with MeCP2 expression (Nat Neurosci. 2011, 14:1607, PMID: 22037496);mutations in MeCP2 are responsible for Rett Syndrome, one of the Pervasive Developmental Disorders linked to Autism. It is possible that the CHD5 complex we have identified is targeted to chromatin through this epigenetic modification. Future: No further work is planned on this project.
