Chromatin remodelers are ATP-dependent DNA translocases that catalyze disassembly, reassembly, and repositioning of nucleosomes throughout eukaryotic genomes. As evidenced from multiple types of cancer and developmental disorders associated with remodeler inactivation, chromatin remodeling is essential for normal growth and development. Remodeling requires transient and controlled disruption of histone-DNA interactions, with different families of remodelers possessing unique domains thought to assist or regulate action of a conserved ATPase motor. Our crystal structure of the Chd1 chromatin remodeler provided the first view of ATPase motor regulation, showing how a DNA-binding surface of the ATPase motor was blocked by adjacent chromodomains. As seen from work with the ISWI remodeler family, the auto-inhibitory nature of the Chd1 chromodomains has proven to be a common strategy for regulating ATPase action on the nucleosome. However, it remains unclear how such domain-domain interactions enable remodelers to sense and respond to particular nucleosome substrates, or achieve unique remodeling outcomes. Here we follow up our recent discoveries of Chd1 architecture on the nucleosome, where the Chd1 DNA-binding domain was found to directly communicate with the chromo-ATPase across the gyres of the nucleosome. We propose to test the hypothesis that inter-domain interactions of Chd1 are responsible for sensing DNA outside the nucleosome and that domains work together to achieve particular remodeling outcomes. In addition to remodeler regulation, the mechanism by which chromatin remodelers reposition nucleosomes along DNA is also poorly understood. Intriguing single molecule FRET experiments with the ISWI remodeler have revealed step-like and discontinuous movements DNA, suggesting that DNA behaves as a spring on the nucleosome. We will test this idea and further investigate DNA interactions needed for high processive steps that we also observe for Chd1. Together, these studies will provide new mechanistic insights into how chromatin remodelers manipulate the structure of the nucleosome and use domain-domain communication to regulate remodeler action. !

Public Health Relevance

Chromatin remodelers are the enzymes responsible for establishing and maintaining this genome packaging, acting to physically expose or bury particular DNA sequences within genes. Disruptions of chromatin remodelers have been directly linked to cancer and other human diseases, highlighting the important role of chromatin remodeling for proper cellular growth and survival. By uncovering the mechanisms by which chromatin remodelers reshape the physical packaging of the genome, we hope to better understand fundamental processes that are essential for human health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Carter, Anthony D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Arts and Sciences
United States
Zip Code
Winger, Jessica; Bowman, Gregory D (2017) The Sequence of Nucleosomal DNA Modulates Sliding by the Chd1 Chromatin Remodeler. J Mol Biol 429:808-822
Bowman, Gregory D; McKnight, Jeffrey N (2017) Sequence-specific targeting of chromatin remodelers organizes precisely positioned nucleosomes throughout the genome. Bioessays 39:1-8
Qiu, Yupeng; Levendosky, Robert F; Chakravarthy, Srinivas et al. (2017) The Chd1 Chromatin Remodeler Shifts Nucleosomal DNA Bidirectionally as a Monomer. Mol Cell 68:76-88.e6
Nodelman, Ilana M; Bleichert, Franziska; Patel, Ashok et al. (2017) Interdomain Communication of the Chd1 Chromatin Remodeler across the DNA Gyres of the Nucleosome. Mol Cell 65:447-459.e6
Wigley, Dale B; Bowman, Gregory D (2017) A glimpse into chromatin remodeling. Nat Struct Mol Biol 24:498-500
Levendosky, Robert F; Sabantsev, Anton; Deindl, Sebastian et al. (2016) The Chd1 chromatin remodeler shifts hexasomes unidirectionally. Elife 5:
Zucconi, Beth E; Luef, Birgit; Xu, Wei et al. (2016) Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain Ligand I-CBP112. Biochemistry 55:3727-34
Nodelman, Ilana M; Horvath, Kyle C; Levendosky, Robert F et al. (2016) The Chd1 chromatin remodeler can sense both entry and exit sides of the nucleosome. Nucleic Acids Res 44:7580-91
McKnight, Jeffrey N; Tsukiyama, Toshio; Bowman, Gregory D (2016) Sequence-targeted nucleosome sliding in vivo by a hybrid Chd1 chromatin remodeler. Genome Res 26:693-704
Hauk, Glenn; Bowman, Gregory D (2015) Formation of a Trimeric Xpo1-Ran[GTP]-Ded1 Exportin Complex Modulates ATPase and Helicase Activities of Ded1. PLoS One 10:e0131690

Showing the most recent 10 out of 26 publications