The CHD7 protein, mutated in CHARGE syndrome, binds to specific sites on chromatin. P.C. Scacheri¹, F. Tie¹, S.R. Lalani², J.W. Belmont², F.S. Collins³. 1) Genetics, Case Western Reserve University, Cleveland, OH; 2) Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; 3) National Human Genome Research Institute, NIH, Bethesda, MD.
   Babies born with CHARGE syndrome have multiple birth defects including coloboma of the eye, heart malformations, choanal atresia, cleft lip and palate, retardation of growth, genital abnormalities, and ear abnormalities. In 2004 it was shown that de novo mutations in the CHD7 gene (coding for chromodomain helicase DNA-binding protein 7) cause most cases of CHARGE syndrome, but little information has been available about the normal function of the protein. Based on homology to other proteins in the CHD family, we hypothesized that CHD7 is located in the nucleus and is associated with chromatin. To address these hypotheses we made antibodies to CHD7 and tested them by subcellular fractionation and Western blot analysis as well as by chromatin immunoprecipitation on tiled microarrays (ChIP-chip). Our results reveal for the first time that: 1) CHD7 is a nuclear protein; 2) CHD7 is physically associated with chromatin; and 3) CHD7 binds to promoters, at or near transcriptional start sites. The ChIP-chip data also indicate that CHD7 does not bind globally to all promoters, but rather co-localizes to a subset of those specifically marked with methylation of lysine 4 on histone H3 (H3K4me), suggesting that CHD7 targets a specific subset of transcriptionally active genes. Some of the CHD7 target genes, including several genes within the HOXA cluster, suggest clues to mechanisms underlying the complex phenotype of CHARGE syndrome. We hypothesize that CHD7 is involved in transcription regulation, and that haploinsufficiency of CHD7 affects expression of multiple CHD7 target genes during development, leading to birth defects in several organ systems.