A role for CHD5 in cancer was first suggested by genetic mapping studies in neuroblastomas 
. Neuroblastomas frequently harbor a deletion of the short arm of human chromosome 1, and the region shared by most deletions includes the CHD5 gene 
. CHD5 was confirmed as the tumor suppressor in this region, as depletion of CHD5 phenocopied the proliferative defects found with deletions engineered in mice 
. Depletion of CHD5 reduced expression of another tumor suppressor, p19Arf, suggesting that CHD5 mediates its tumor suppressive activity through modulation of the p19arf/p53 pathway 
. Subsequently, CHD5 has been reported to be mutated, deleted or silenced in a variety of human cancers including glioma, leukemia/lymphoma, melanoma, breast, prostate, ovarian and gastric cancers 
. CHD5 expression has been suggested to serve as a biomarker for positive outcomes in neuroblastoma patients 
Chromodomain/helicase/DNA-binding domain (CHD) proteins are found in eukaryotes from yeast through humans 
. 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 tandem chromodomains of CHD1 specifically recognize H3K4Me3 and can facilitate the recruitment of post-transcriptional initiation and splicing factors 
. The human CHD family is often divided by sequence homology: subfamily I (CHD1 and CHD2), subfamily II (CHD3 and CHD4) and subfamily III (CHD6, CHD7, CHD8, CHD9); CHD5 has been grouped with CHD 6–9 by some authors, and CHD 3–4 by others 
. Many remodeling ATPases are expressed ubiquitously in the body plan. CHD5 is unusual in that its expression is reported to be limited to the developing brain, adult brain and the adrenal gland, suggesting a potential role in the development or function of the neural system 
. Deletion of a region of chromosome 1 near CHD5 has been linked to intellectual impairment 
. However, the role of CHD5 in brain development and function remains to be determined.
CHD3 and CHD4, also known as Mi-2alpha and Mi-2ß, are found in multiprotein chromatin remodeling complexes named NuRD 
. In addition to the ATPase activity of the CHD subunit, NuRD complexes include the histone deacetylases HDAC1 and HDAC2. NuRD complexes include a methyl CpG binding protein (MBD2 or MBD3), adapter proteins (RbAp46 and/or RbAp48), p66, and a metastasis associated protein (MTA1, 2 or 3).
CHD proteins have been demonstrated to regulate gene expression, with CHD3 and CHD4 being the best-studied examples 
. NuRD is often described as a transcriptional repressor, in part because of the presence of histone deacetylase activity. However, NuRD complex activity results in divergent outcomes for two target genes in developing lymphocytes, mb-1 and CD4: NuRD inhibits mb-1 transcription and activates CD4 transcription 
. NuRD is also an activator and repressor during blood development 
. This behavior is reminiscent of the mammalian ISWI remodelers, which are also often thought of as repressors, yet appear to possess activation potential as well 
. How the NuRD complex can differentially regulate gene transcription remains an open question but it has been suggested to be an outcome of a regulated shift in the composition of NuRD components or through the association with other transcriptional regulators. Genome-wide analysis of Mi2 binding in D. melanogaster
revealed association with regions that appeared to be enhancers and promoters 
. Less is known about the potential chromatin remodeling and gene regulatory functions of CHD5–CHD9. Whether CHD5 exists in a multi-protein complex and functions to regulate gene expression in the brain has not been reported.
Remodeling of chromatin structure is an important determinant of cell fate decisions and function in the nervous system. In particular, ATP-dependent remodeling has been shown to be critical for the development of invertebrate and vertebrate nervous systems 
. The best-characterized example is SWI/SNF, containing the BRG1 and BRM ATPases. The SWI/SNF ATPases are ubiquitous, though the accessory proteins in the complex are developmentally regulated. During the transition from neural progenitor to post-mitotic neuron, BAF45a and BAF53a are replaced by BAF45b and BAF53b to assemble the brain-specific nBAF form of the SWI/SNF complex 
. nBAF is critical in neuron-specific function as BAF53b-deficient mice have a defect in neuron dendrite outgrowth 
. In addition to ATP-dependent remodeling, HDAC-inhibitor studies revealed a role for chromatin remodeling involving histone acetylation in synaptic plasticity and learning behaviors 
. Studies on HDAC2-deficient mice implicated this particular deacetylase as a direct negative regulator of learning and memory 
Here, we examine CHD5 in rodent brain and neurons. We found CHD5 was present in a multiprotein NuRD-like complex. CHD5 was expressed in several brain regions, and CHD5 was found in neurons. Depletion of CHD5 from primary neurons revealed genes that were activated and repressed by CHD5. The targets included genes that were previously identified as important for aging, Alzheimer's disease, and neuronal development. Binding of CHD5 to some of these target genes in intact cells suggested they were directly regulated by CHD5.