CRAMP1 drives linker histone expression to enable Polycomb repression
In contrast to the well-understood role of core histones in DNA packaging, the function of the linker histone (H1) remains enigmatic. Challenging the prevailing view that linker histones are a general feature of heterochromatin, here we show a critical requirement for H1 in Polycomb repressive complex 2 (PRC2) function. A CRISPR-Cas9 genetic screen using a fluorescent PRC2 reporter identified an essential role for the poorly characterized gene CRAMP1 in PRC2-mediated repression. CRAMP1 localizes to the promoters of expressed H1 genes and positively regulates their transcription. CRAMP1 ablation simultaneously depletes all linker histones, which results in selective decompaction of H3K27me3-marked loci and derepression of PRC2 target genes without concomitant loss of PRC2 occupancy or enzymatic activity. Strikingly, we find that linker histones preferentially localize to genomic loci marked by H3K27me3 across diverse cell types and organisms. Altogether, these data demonstrate a prominent role for linker histones in epigenetic repression by PRC2.
Authors
- Rachael E. Matthews
- Ankit Verma (ORCID: https://orcid.org/0000-0002-9791-4997)
- Boyan Bonev (ORCID: https://orcid.org/0000-0002-7502-9399)
- John Suberu (ORCID: https://orcid.org/0000-0003-3419-0925)
- Akhila Gungi (ORCID: https://orcid.org/0000-0002-2244-4599)
- Julie Ahringer (ORCID: https://orcid.org/0000-0002-7074-4051)
- Richard T. Timms (ORCID: https://orcid.org/0000-0001-7275-597X)
- Adam J. Reid
- Mark A. Dawson (ORCID: https://orcid.org/0000-0002-5464-5029)
- Toby Buttress (ORCID: https://orcid.org/0000-0001-5643-3508)
- Faye Chong (ORCID: https://orcid.org/0000-0002-5414-9746)
- Alex Appert
- Robin Antrobus (ORCID: https://orcid.org/0000-0001-8608-4011)
- Laura Smith
- Oliver Sinclair (ORCID: https://orcid.org/0000-0002-0904-4566)
- Iva A. Tchasovnikarova (ORCID: https://orcid.org/0000-0002-0477-0956)
- Sri Rahayu Lestari (ORCID: https://orcid.org/0000-0003-2208-4156)
- Joshua Miguel C. Danac
- Emily L Naden
Institutions
- University of Cambridge (GB)
- Peter MacCallum Cancer Centre (AU)
- The Gurdon Institute (GB)
- Helmholtz Zentrum München (DE)
- Addenbrooke's Hospital (GB)
- MRC Epidemiology Unit (GB)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Molecular Cell
- Published
- 2025-06-13
- DOI
- https://doi.org/10.1016/j.molcel.2025.05.031
- Citations
- 8
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 6.45
Funders
- Wellcome
- Cancer Research UK