Structural mechanism of HP1⍺-dependent transcriptional repression and chromatin compaction
Open accessPublished version of a preprint
Abstract
Heterochromatin protein 1 (HP1) plays a central role in establishing and maintaining constitutive heterochromatin. However, the mechanisms underlying HP1-nucleosome interactions and their contributions to heterochromatin functions remain elusive. In this study, we employed a multidisciplinary approach to unravel the interactions between human HP1α and nucleosomes. We have elucidated the cryo-EM structure of an HP1α dimer bound to an H2A.Z nucleosome, revealing that the HP1α dimer interfaces with nucleosomes at two distinct sites. The primary binding site is located at the N-terminus of histone H3, specifically at the trimethylated K9 (K9me3) region, while a novel secondary binding site is situated near histone H2B, close to nucleosome superhelical location 4 (SHL4). Our biochemical data further demonstrates that HP1α binding influences the dynamics of DNA on the nucleosome. It promotes DNA unwrapping near the nucleosome entry and exit sites while concurrently restricting DNA accessibility in the vicinity of SHL4. This study offers a model that explains how HP1α functions in heterochromatin maintenance and gene silencing, particularly in the context of H3K9me-dependent mechanisms. Additionally, it sheds light on the H3K9me-independent role of HP1 in responding to DNA damage.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
ATM Signaling Facilitates Repair of DNA Double-Strand Breaks Associated with Heterochromatin
Goodarzi, A. A., Noon, A. T., Deckbar, D., Ziv, Y., Shiloh, Y., Löbrich, M., & Jeggo, P. A. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.05.017 · Cited by 836 · see citing works
Heterochromatin protein 1 is recruited to various types of DNA damage
Luijsterburg, M. S., Dinant, C., Lans, H., Stap, J., Wiernasz, E., Lagerwerf, S., Warmerdam, D. O., Lindh, M., Brink, M. C., Dobrucki, J. W., et al. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200810035 · Cited by 264 · see citing works
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- Authors
- Sokolova, V., Miratsky, J., Svetlov, V., Brenowitz, M., Vant, J., Lewis, T. S., Dryden, K., Lee, G., Sarkar, S., Nudler, E., Singharoy, A., & Tan, D.
- Affiliations
- Stony Brook University (US)
- Arizona State University (US)
- Howard Hughes Medical Institute (US)
- Albert Einstein College of Medicine (US)
- University of Virginia (US)
- Corresponding author
- Tan, Dongyan
- ORCID
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2024-11
- Volume
- 32
- Issue
- 11
- Pages
- 2094-2106.e6
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC11560701
- OpenAlex
- W4403223236
- Cited by
- 11
- References
- 3
- Citations by year
- 2026: 7 · 2025: 4
- FWCI
- 1.50
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Structure (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Biological and Environmental Research (KP1607011)
- National Science Foundation (1S10OD012272-01A1, SCR_019031, 1942049)
- National Institutes of Health (1R35GM133611, U24 GM116790, 1S10OD012272-01A1)
- School of Medicine, University of Utah Health (U24-GM116790, G20-RR31199, S10-RR025067)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- HP1α, HP1, transcriptional repression, chromatin condensation, heterochromatin maintenance, DNA accessibility, gene silencing, DNA damage response
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