CHD1 explained

The Chromodomain-Helicase DNA-binding 1 is a protein that, in humans, is encoded by the CHD1 gene.^{[1] [2] [3]} 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).^{[4] [5]}

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. The catalytic domain of CHD1, which is highly conserved across all nucleosome remodelers, is a two-lobed structure. CHD1 relies on the DNA-binding domain, which binds DNA in a sequence non-specific manner, to help regulate spacing.^[6]

CHD1 is a member of a large family of CHD nucleosome remodelers, though yeast has only one CHD protein, called Chd1.^[7] Humans and mice, by contrast, have ten CHD proteins that are homologous to CHD1, but each have their own characteristic functions.^[8]

Structure

CHD1 contains two tandem N-terminal chromodomains, a SNF2-related domain, a helicase C domain, CDH1/2 SANT-Helical linker, and a disordered C-terminal region.^[9]

The structure of Chd1 bound to the nucleosome has been solved (Figure 2).

Function

CHD1 is essential for embryonic stem cell pluripotency in mice by maintaining an open euchromatic chromatin state.^[10] Chd1 helps maintain boundaries between histone modifications H3K4me3 and H3K36me3.^[11] It has also been shown that CHD1 is important in dictating the transcriptional landscape by promoting differentiation of osteoblasts, or differentiating bone cells.^[12] 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. ^{[13] [14]}

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).^[15] 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).^[16] Structural information has shown that the Chd1 chromodomains in yeast do not bind H3K4me3.

CHD1 has been shown to interact with Nuclear receptor co-repressor 1.^[17]

Clinical significance

CHD1 is most notably implicated in prostate cancer development. In about 10% of all prostate cancers, CHD1 is mutated or deleted.^{[18] [19]} 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. 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.^[20]

Further reading

• Stokes DG, Perry RP . DNA-binding and chromatin localization properties of CHD1 . Molecular and Cellular Biology . 15 . 5 . 2745–53 . May 1995 . 7739555 . 230505 . 10.1128/mcb.15.5.2745 .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Kelley DE, Stokes DG, Perry RP . 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 . April 1999 . 10199952 . 10.1007/s004120050347 . 12945778 .
• Salomon AR, Ficarro SB, Brill LM, Brinker A, Phung QT, Ericson C, Sauer K, Brock A, Horn DM, Schultz PG, Peters EC . 6 . Profiling of tyrosine phosphorylation pathways in human cells using mass spectrometry . Proceedings of the National Academy of Sciences of the United States of America . 100 . 2 . 443–8 . January 2003 . 12522270 . 141014 . 10.1073/pnas.2436191100 . 2003PNAS..100..443S . free .
• Tai HH, Geisterfer M, Bell JC, Moniwa M, Davie JR, Boucher L, McBurney MW . CHD1 associates with NCoR and histone deacetylase as well as with RNA splicing proteins . Biochemical and Biophysical Research Communications . 308 . 1 . 170–6 . August 2003 . 12890497 . 10.1016/S0006-291X(03)01354-8 .
• Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW . 6 . Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation . Nature Biotechnology . 22 . 6 . 707–16 . June 2004 . 15146197 . 10.1038/nbt971 . 27764390 .
• Sims RJ, Chen CF, Santos-Rosa H, Kouzarides T, Patel SS, Reinberg D . Human but not yeast CHD1 binds directly and selectively to histone H3 methylated at lysine 4 via its tandem chromodomains . The Journal of Biological Chemistry . 280 . 51 . 41789–92 . December 2005 . 16263726 . 1421377 . 10.1074/jbc.C500395200 . free .
• Flanagan JF, Mi LZ, Chruszcz M, Cymborowski M, Clines KL, Kim Y, Minor W, Rastinejad F, Khorasanizadeh S . 6 . Double chromodomains cooperate to recognize the methylated histone H3 tail . Nature . 438 . 7071 . 1181–5 . December 2005 . 16372014 . 10.1038/nature04290 . 4401500 . 2005Natur.438.1181F .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .
• Okuda M, Horikoshi M, Nishimura Y . Structural polymorphism of chromodomains in Chd1 . Journal of Molecular Biology . 365 . 4 . 1047–62 . January 2007 . 17098252 . 10.1016/j.jmb.2006.10.039 .
• Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D . 6 . Large-scale mapping of human protein-protein interactions by mass spectrometry . Molecular Systems Biology . 3 . 1 . 89 . 2007 . 17353931 . 1847948 . 10.1038/msb4100134 .

Notes and References

1. Delmas V, Stokes DG, Perry RP . A mammalian DNA-binding protein that contains a chromodomain and an SNF2/SWI2-like helicase domain . Proceedings of the National Academy of Sciences of the United States of America . 90 . 6 . 2414–8 . March 1993 . 8460153 . 46097 . 10.1073/pnas.90.6.2414 . 1993PNAS...90.2414D . free .
2. Woodage T, Basrai MA, Baxevanis AD, Hieter P, Collins FS . Characterization of the CHD family of proteins . Proceedings of the National Academy of Sciences of the United States of America . 94 . 21 . 11472–7 . October 1997 . 9326634 . 23509 . 10.1073/pnas.94.21.11472 . 1997PNAS...9411472W . free .
3. Web site: Entrez Gene: CHD1 chromodomain helicase DNA binding protein 1.
4. Clapier CR, Iwasa J, Cairns BR, Peterson CL . Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes . Nature Reviews. Molecular Cell Biology . 18 . 7 . 407–422 . July 2017 . 28512350 . 10.1038/nrm.2017.26 . 8127953 .
5. Farnung L, Vos SM, Wigge C, Cramer P . Nucleosome-Chd1 structure and implications for chromatin remodelling . Nature . 550 . 7677 . 539–542 . October 2017 . 29019976 . 5697743 . 10.1038/nature24046 . 2017Natur.550..539F .
6. Hauk G, McKnight JN, Nodelman IM, Bowman GD . The chromodomains of the Chd1 chromatin remodeler regulate DNA access to the ATPase motor . Molecular Cell . 39 . 5 . 711–23 . September 2010 . 20832723 . 2950701 . 10.1016/j.molcel.2010.08.012 .
7. Flanagan JF, Blus BJ, Kim D, Clines KL, Rastinejad F, Khorasanizadeh S . Molecular implications of evolutionary differences in CHD double chromodomains . Journal of Molecular Biology . 369 . 2 . 334–42 . June 2007 . 17433364 . 1948097 . 10.1016/j.jmb.2007.03.024 .
8. Cheng W, Su Y, Xu F . CHD1L: a novel oncogene . Molecular Cancer . 12 . 1 . 170 . December 2013 . 24359616 . 3931672 . 10.1186/1476-4598-12-170 . free .
9. Web site: CHD1_HUMAN (O14646) . InterPro . European Molecular Biology Laboratory.
10. Gaspar-Maia A, Alajem A, Polesso F, Sridharan R, Mason MJ, Heidersbach A, Ramalho-Santos J, McManus MT, Plath K, Meshorer E, Ramalho-Santos M . 6 . Chd1 regulates open chromatin and pluripotency of embryonic stem cells . Nature . 460 . 7257 . 863–8 . August 2009 . 19587682 . 3891576 . 10.1038/nature08212 . 2009Natur.460..863G .
11. Lee Y, Park D, Iyer VR . The ATP-dependent chromatin remodeler Chd1 is recruited by transcription elongation factors and maintains H3K4me3/H3K36me3 domains at actively transcribed and spliced genes . Nucleic Acids Research . 45 . 12 . 7180–7190 . July 2017 . 28460001 . 5499586 . 10.1093/nar/gkx321 .
12. Baumgart SJ, Najafova Z, Hossan T, Xie W, Nagarajan S, Kari V, Ditzel N, Kassem M, Johnsen SA . 6 . CHD1 regulates cell fate determination by activation of differentiation-induced genes . Nucleic Acids Research . 45 . 13 . 7722–7735 . July 2017 . 28475736 . 5570082 . 10.1093/nar/gkx377 .
13. Gnugnoli . M . Casari . E . Longhese . MP . The chromatin remodeler Chd1 supports MRX and Exo1 functions in resection of DNA double-strand breaks . PLOS Genetics . September 2021 . 17 . 9 . e1009807 . 10.1371/journal.pgen.1009807. 34520455 . 8462745 . free .
14. Kari . V . Mansour . WY . Raul . SK . Baumgart . SJ . Mund . A . Grade . M . Sirma . H . Simon . R . Will . H . Dobbelstein . M . Dikomey . E . Johnsen . SA . Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness. . EMBO Reports . November 2016 . 17 . 11 . 1609–1623 . 10.15252/embr.201642352 . 27596623. 5090703 .
15. Flanagan JF, Mi LZ, Chruszcz M, Cymborowski M, Clines KL, Kim Y, Minor W, Rastinejad F, Khorasanizadeh S . 6 . Double chromodomains cooperate to recognize the methylated histone H3 tail . Nature . 438 . 7071 . 1181–5 . December 2005 . 16372014 . 10.1038/nature04290 . 2005Natur.438.1181F . 4401500 .
16. Simic R, Lindstrom DL, Tran HG, Roinick KL, Costa PJ, Johnson AD, Hartzog GA, Arndt KM . 6 . Chromatin remodeling protein Chd1 interacts with transcription elongation factors and localizes to transcribed genes . The EMBO Journal . 22 . 8 . 1846–56 . April 2003 . 12682017 . 154471 . 10.1093/emboj/cdg179 .
17. Tai HH, Geisterfer M, Bell JC, Moniwa M, Davie JR, Boucher L, McBurney MW . CHD1 associates with NCoR and histone deacetylase as well as with RNA splicing proteins . Biochemical and Biophysical Research Communications . 308 . 1 . 170–6 . August 2003 . 12890497 . 10.1016/S0006-291X(03)01354-8 .
18. Zhao D, Lu X, Wang G, Lan Z, Liao W, Li J, Liang X, Chen JR, Shah S, Shang X, Tang M, Deng P, Dey P, Chakravarti D, Chen P, Spring DJ, Navone NM, Troncoso P, Zhang J, Wang YA, DePinho RA . 6 . Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer . Nature . 542 . 7642 . 484–488 . February 2017 . 28166537 . 5448706 . 10.1038/nature21357 . 2017Natur.542..484Z .
19. Huang S, Gulzar ZG, Salari K, Lapointe J, Brooks JD, Pollack JR . Recurrent deletion of CHD1 in prostate cancer with relevance to cell invasiveness . Oncogene . 31 . 37 . 4164–70 . September 2012 . 22179824 . 5512870 . 10.1038/onc.2011.590 .
20. Augello MA, Liu D, Deonarine LD, Robinson BD, Huang D, Stelloo S, Blattner M, Doane AS, Wong EW, Chen Y, Rubin MA, Beltran H, Elemento O, Bergman AM, Zwart W, Sboner A, Dephoure N, Barbieri CE . 6 . CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis . Cancer Cell . 35 . 4 . 603–617.e8 . April 2019 . 30930119 . 6467783 . 10.1016/j.ccell.2019.03.001 .