The Chromodomain-Helicase DNA-binding 1 is a protein that, in humans, is encoded by the CHD1 gene.[5][6][7] CHD1 is a chromatin remodeling protein that is widely conserved across many eukaryotic organisms, from yeast to humans. CHD1 is named for three of its protein domains: two tandem chromodomains, its ATPase catalytic domain, and its DNA-binding domain (Figure 1).[8][9]
The CHD1 remodeler binds nucleosomes and induces local changes in nucleosome positioning through ATP hydrolysis coupled to DNA translocation of the DNA across the histone 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 nine CHD proteins that are homologous to S. cerevisiae Chd1, but each have their own characteristic functions.[11][12] There are a total of three subfamilies of CHD remodelers in humans. CHD1, together with CHD2, belong to subfamily 1.
Structure
CHD1 contains two N-terminal tandem chromodomains, a SNF2-related domain, a helicase C domain, a DNA-binding 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).
In 2017, the structure of S. cerevisiae Chd1 bound to the nucleosome has been obtained using single-particle cryo-EM by Lucas Farnung in the lab of Patrick Cramer (Figure 2).[9] In 2025, the laboratory of Lucas Farnung at Harvard Medical School provided the structure of human CHD1 bound to a nucleosome[14].
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.
Function
CHD1 is essential for embryonic stem cell pluripotency in mice by maintaining an open euchromatic chromatin state.[15] Chd1 helps maintain boundaries between histone modifications H3K4me3 and H3K36me3.[16] It has also been shown that CHD1 is important in dictating the transcriptional landscape by promoting differentiation of osteoblasts, or differentiating bone cells.[17] 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. [18][19]
Interactions
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).[20] 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 with Rtf1, a transcription elongation factor and member of the Paf1 Complex (Paf1C).[21] Structural information has shown that the Chd1 chromodomains in yeast do not bind H3K4me3.[11] The human protein binds H3K4me3. Human CHD1 shows little difference in binding and remodeling activity on H3K4me3-containing versus non-H3K4 trimethylated nucleososomes in vitro.[22]
CHD1 is most notably implicated in prostate cancer development. In about 10% of all prostate cancers, CHD1 is mutated or deleted.[24][25] In prostate cancer cells CHD1 also has an essential relationship with another cancer driver, the PTEN locus. In studies of prostate cancer patient data, when PTEN is mutated, Chd1 gains an essential role and is never deleted.[24] 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.[26]
↑ James, AM; Farnung, L (15 May 2025). "Structural basis of human CHD1 nucleosome recruitment and pausing". Molecular cell. 85 (10): 1938-1951.e6. doi:10.1016/j.molcel.2025.04.020. PMID40334658.
↑ James, AM; Farnung, L (15 May 2025). "Structural basis of human CHD1 nucleosome recruitment and pausing". Molecular cell. 85 (10): 1938-1951.e6. doi:10.1016/j.molcel.2025.04.020. PMID40334658.
↑ 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, etal. (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.
2b2t: Tandem chromodomains of human CHD1 complexed with Histone H3 Tail containing trimethyllysine 4 and phosphothreonine 3
2b2u: Tandem chromodomains of human CHD1 complexed with Histone H3 Tail containing trimethyllysine 4 and dimethylarginine 2
2b2v: Crystal structure analysis of human CHD1 chromodomains 1 and 2 bound to histone H3 resi 1-15 MeK4
2b2w: Tandem chromodomains of human CHD1 complexed with Histone H3 Tail containing trimethyllysine 4
2b2y: Tandem chromodomains of human CHD1
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