Abstract
The packaging of DNA into chromatin in eukaryotes regulates gene transcription, DNA replication and DNA repair. ATP-dependent chromatin remodelling enzymes (re)arrange nucleosomes at the first level of chromatin organization. Their Snf2-type motor ATPases alter histone–DNA interactions through a common DNA translocation mechanism. Whether remodeller activities mainly catalyse nucleosome dynamics or accurately co-determine nucleosome organization remained unclear. In this Review, we discuss the emerging mechanisms of chromatin remodelling: dynamic remodeller architectures and their interactions, the inner workings of the ATPase cycle, allosteric regulation and pathological dysregulation. Recent mechanistic insights argue for a decisive role of remodellers in the energy-driven self-organization of chromatin, which enables both stability and plasticity of genome regulation — for example, during development and stress. Different remodellers, such as members of the SWI/SNF, ISWI, CHD and INO80 families, process (epi)genetic information through specific mechanisms into distinct functional outputs. Combinatorial assembly of remodellers and their interplay with histone modifications, histone variants, DNA sequence or DNA-bound transcription factors regulate nucleosome mobilization or eviction or histone exchange. Such input–output relationships determine specific nucleosome positions and compositions with distinct DNA accessibilities and mediate differential genome regulation. Finally, remodeller genes are often mutated in diseases characterized by genome dysregulation, notably in cancer, and we discuss their physiological relevance.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 309-332 |
| Number of pages | 24 |
| Journal | Nature Reviews Molecular Cell Biology |
| Volume | 25 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2024 |
Funding
Animations were created by G. Hsu and J. Iwasa based on many enjoyable and insightful discussions. We gratefully acknowledge input from colleagues, especially from G. Narlikar on energetics of remodeller mechanisms, D. Herschlag on coupled vectorial processes, J.s Buchner and F. U. Hartl on molecular chaperones, R. Louder on remodeller compositions and P. Becker on remodellers by and large. This work was funded by NIGMS (R01GM135651 and R01GM144559 to Y.H.), the German Research Foundation (SFB/CRC1064 \u2018Chromatin dynamics\u2019 to P.K. and K.P.H.) and the European Molecular Biology Laboratory (S.E.). We especially appreciate cofunding the costs of generating animations by the German Research Foundation\u2019s grant SFB/CRC1064 to P.K. and K.-P.H.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
