Structural mechanism of HP1⍺-dependent transcriptional repression and chromatin compaction

Vladyslava Sokolova; Jacob Miratsky; Vladimir Svetlov; Michael Brenowitz; John Vant; Tyler S. Lewis; Kelly Dryden; Gahyun Lee; Shayan Sarkar; Evgeny Nudler; Abhishek Singharoy; Dongyan Tan

doi:10.1016/j.str.2024.09.013

Structural mechanism of HP1⍺-dependent transcriptional repression and chromatin compaction

Vladyslava Sokolova, Jacob Miratsky, Vladimir Svetlov, Michael Brenowitz, John Vant, Tyler S. Lewis, Kelly Dryden, Gahyun Lee, Shayan Sarkar, Evgeny Nudler, Abhishek Singharoy, Dongyan Tan

Research output: Contribution to journal › Article › peer-review

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. Here, we present the cryoelectron microscopy (cryo-EM) structure of an HP1α dimer bound to an H2A.Z-nucleosome, revealing two distinct HP1α-nucleosome interfaces. The primary HP1α binding site is located at the N terminus of histone H3, specifically at the trimethylated lysine 9 (K9me3) region, while a 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. Our study offers a model for HP1α-mediated heterochromatin maintenance and gene silencing. It also sheds light on the H3K9me-independent role of HP1 in responding to DNA damage.

Original language	English
Journal	Structure
DOIs	https://doi.org/10.1016/j.str.2024.09.013
State	Accepted/In press - 2024
Externally published	Yes

Funding

We thank the staff in the Laboratory for BioMolecular Structure (LBMS) for help in data collection. LBMS is supported by the DOE Office of Biological and Environmental Research ( KP1607011 ). This work was also supported by: NIH grant 1R35GM133611 to D.T.NSF grant 1942049 to D.T. Access to the additional instrumentation was supported by the following grants: NIH grant U24 GM116790 to M.Y. and D.T., NIH grant 1S10OD012272-01A1 to H.L. We thank the staff in the Laboratory for BioMolecular Structure (LBMS) for help in data collection. LBMS is supported by the DOE Office of Biological and Environmental Research (KP1607011). This work was also supported by: NIH grant 1R35GM133611 to D.T. NSF grant 1942049 to D.T. Access to the additional instrumentation was supported by the following grants: NIH grant U24 GM116790 to M.Y. and D.T., NIH grant 1S10OD012272-01A1 to H.L. Transmission electron micrographs were recorded at the University of Virginia Molecular Electron Microscopy Core facility (RRID:SCR_019031), which is supported in part by the School of Medicine and built with NIH grant G20-RR31199. In addition, the Titan Krios (S10-RR025067) and K3/GIF (U24-GM116790) were purchased in part or in full with the designated NIH grants.

Funders	Funder number
Biological and Environmental Research	KP1607011
Biological and Environmental Research
School of Medicine, University of Utah Health	U24-GM116790, S10-RR025067, G20-RR31199
School of Medicine, University of Utah Health
National Institutes of Health	1942049, 1S10OD012272-01A1, U24 GM116790, 1R35GM133611
National Institutes of Health
National Science Foundation	1S10OD012272-01A1, SCR_019031
National Science Foundation

Keywords

cryo-EM
heterochromatin
histone methylation
histone variant
HP
MDFF
nucleosome

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10.1016/j.str.2024.09.013

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title = "Structural mechanism of HP1⍺-dependent transcriptional repression and chromatin compaction",

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. Here, we present the cryoelectron microscopy (cryo-EM) structure of an HP1α dimer bound to an H2A.Z-nucleosome, revealing two distinct HP1α-nucleosome interfaces. The primary HP1α binding site is located at the N terminus of histone H3, specifically at the trimethylated lysine 9 (K9me3) region, while a 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. Our study offers a model for HP1α-mediated heterochromatin maintenance and gene silencing. It also sheds light on the H3K9me-independent role of HP1 in responding to DNA damage.",

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author = "Vladyslava Sokolova and Jacob Miratsky and Vladimir Svetlov and Michael Brenowitz and John Vant and Lewis, {Tyler S.} and Kelly Dryden and Gahyun Lee and Shayan Sarkar and Evgeny Nudler and Abhishek Singharoy and Dongyan Tan",

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year = "2024",

doi = "10.1016/j.str.2024.09.013",

language = "English",

journal = "Structure",

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T1 - Structural mechanism of HP1⍺-dependent transcriptional repression and chromatin compaction

AU - Sokolova, Vladyslava

AU - Miratsky, Jacob

AU - Svetlov, Vladimir

AU - Brenowitz, Michael

AU - Vant, John

AU - Lewis, Tyler S.

AU - Dryden, Kelly

AU - Lee, Gahyun

AU - Sarkar, Shayan

AU - Nudler, Evgeny

AU - Singharoy, Abhishek

AU - Tan, Dongyan

PY - 2024

Y1 - 2024

N2 - 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. Here, we present the cryoelectron microscopy (cryo-EM) structure of an HP1α dimer bound to an H2A.Z-nucleosome, revealing two distinct HP1α-nucleosome interfaces. The primary HP1α binding site is located at the N terminus of histone H3, specifically at the trimethylated lysine 9 (K9me3) region, while a 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. Our study offers a model for HP1α-mediated heterochromatin maintenance and gene silencing. It also sheds light on the H3K9me-independent role of HP1 in responding to DNA damage.

AB - 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. Here, we present the cryoelectron microscopy (cryo-EM) structure of an HP1α dimer bound to an H2A.Z-nucleosome, revealing two distinct HP1α-nucleosome interfaces. The primary HP1α binding site is located at the N terminus of histone H3, specifically at the trimethylated lysine 9 (K9me3) region, while a 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. Our study offers a model for HP1α-mediated heterochromatin maintenance and gene silencing. It also sheds light on the H3K9me-independent role of HP1 in responding to DNA damage.

KW - cryo-EM

KW - heterochromatin

KW - histone methylation

KW - histone variant

KW - HP

KW - MDFF

KW - nucleosome

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U2 - 10.1016/j.str.2024.09.013

DO - 10.1016/j.str.2024.09.013

M3 - Article

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SN - 0969-2126

JO - Structure

JF - Structure

ER -

Structural mechanism of HP1⍺-dependent transcriptional repression and chromatin compaction

Abstract

Funding

Keywords

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