TheChromodomain-Helicase DNA-binding 1 is aprotein that, in humans, is encoded by the CHD1gene.[5][6][7] CHD1 is achromatin remodeling protein that is widely conserved across many eukaryotic organisms, from yeast to humans. CHD1 is named for three of its protein domains: two tandemchromodomains, itsATPase catalytic domain, and itsDNA-binding domain (Figure 1).[8][9]
The CHD1 remodeler bindsnucleosomes and induces local changes in nucleosome positioning throughATP hydrolysis coupled to DNA translocation of the DNA across thehistone proteins.[8] The catalytic domain of CHD1, which is highly conserved across all nucleosome remodelers, is a two-lobed structure.[8] CHD1 relies on the DNA-binding domain, which binds DNA in a sequence non-specific manner, to help regulate spacing.[10]
CHD1 is a member of a large family of CHD nucleosome remodelers, though yeast has only one CHD protein, called Chd1.[11] Humans and mice, by contrast, have ten CHD proteins that are homologous to CHD1, but each have their own characteristic functions.[11][12]
CHD1 contains two tandem N-terminalchromodomains, a SNF2-related domain, a helicase C domain, CDH1/2 SANT-Helical linker, and a disordered C-terminal region.[13]
Figure 1. Schematic of the Chd1 protein, with tandem chromodomains (purple), ATPase catalytic domain (orange) and DNA binding domain (pink) bound to the nucleosome (DNA in blue, histones in green).
The structure of Chd1 bound to the nucleosome has been solved (Figure 2).[9]
Figure 2. Cryo-EM structure of Chd1 bound to the nucleosome, including the chromodomains (purple), ATPase domain (orange) and DNA-binding domain (pink), with histone octamer (green) and DNA (blue). PDB: 5O9G.
CHD1 is essential for embryonic stem cell pluripotency in mice by maintaining an openeuchromatic chromatin state.[14] Chd1 helps maintain boundaries between histone modificationsH3K4me3 andH3K36me3.[15] It has also been shown that CHD1 is important in dictating the transcriptional landscape by promoting differentiation ofosteoblasts, or differentiating bone cells.[16] Studies in both yeast and humans have found that Chd1 is recruited to DNA damage sites, where it promotes the opening of chromatin and the recruitment of DNA repair factors, thus facilitating DNA repair by homologous recombination.[17][18]
CHD1 has several genetic interactions with numerous factors involved in chromatin maintenance and transcription. Notably, the chromodomains of human CHD1 are capable of binding the histone modification histone H3 Lysine 4 trimethyl (H3K4me3).[19] It is thought that human CHD1 preferentially binds this histone modification, which is primarily located at the 5’ regions of genes, as a mechanism of recruitment to those genomic loci. However, in yeast it has been shown that Chd1 interacts withRtf1, a transcription elongation factor and member of the Paf1 Complex (Paf1C).[20] Structural information has shown that the Chd1 chromodomains in yeast do not bind H3K4me3.[11]
CHD1 is most notably implicated in prostate cancer development. In about 10% of all prostate cancers, CHD1 is mutated or deleted.[22][23] In prostate cancer cells CHD1 also has an essential relationship with another cancer driver, thePTEN locus. In studies of prostate cancer patient data, whenPTEN is mutated, Chd1 gains an essential role and is never deleted.[22] Thus, CHD1 misfunction is evident in the majority of prostate cancers. Further, mutation of CHD1 alone is sufficient in some mice models to induce prostate tumorigenesis.[24]
^Tai HH, Geisterfer M, Bell JC, Moniwa M, Davie JR, Boucher L, McBurney MW (August 2003). "CHD1 associates with NCoR and histone deacetylase as well as with RNA splicing proteins".Biochemical and Biophysical Research Communications.308 (1):170–6.doi:10.1016/S0006-291X(03)01354-8.PMID12890497.
Kelley DE, Stokes DG, Perry RP (April 1999). "CHD1 interacts with SSRP1 and depends on both its chromodomain and its ATPase/helicase-like domain for proper association with chromatin".Chromosoma.108 (1):10–25.doi:10.1007/s004120050347.PMID10199952.S2CID12945778.
Tai HH, Geisterfer M, Bell JC, Moniwa M, Davie JR, Boucher L, McBurney MW (August 2003). "CHD1 associates with NCoR and histone deacetylase as well as with RNA splicing proteins".Biochemical and Biophysical Research Communications.308 (1):170–6.doi:10.1016/S0006-291X(03)01354-8.PMID12890497.
Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, et al. (June 2004). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation".Nature Biotechnology.22 (6):707–16.doi:10.1038/nbt971.PMID15146197.S2CID27764390.
Okuda M, Horikoshi M, Nishimura Y (January 2007). "Structural polymorphism of chromodomains in Chd1".Journal of Molecular Biology.365 (4):1047–62.doi:10.1016/j.jmb.2006.10.039.PMID17098252.
