Signaling induced biophysical disruption of repressed chromatin domains drives immune cell fate
Cell fate transitions require signal-induced chromatin derepression, yet mechanisms governing transitions from repressed to active chromatin states are poorly understood. We discover, at fate-defining genes across immune cell types, a signal-induced histone code, and describe domains of H3 serine 28 phosphorylation (H3S28ph) spanning architectural features, often coincident with repressive H3 lysine 27 trimethylation (H3K27me3). Employing biophysical, single cell, and functional approaches to study signal-induced cell differentiation in the immune system, we uncover epigenomic transitions and cell fate choices precipitated by histone phosphorylation (H3ph). Mechanistically, H3ph overrides Polycomb Repressive Complex 2 (PRC2) chromatin repression, biophysically disrupts polynucleosome compaction, and promotes loss of H3K27me3, while increasing activating H3K27 acetylation and H3K36 dimethylation to drive domain interactivity and stabilize transcription. We demonstrate the activity of H3ph in several cell fate transitions and illuminate biophysical mechanisms enabling rapid signal-activated chromatin derepression, processes with general relevance for cellular differentiation and activation.
Authors
- Michael‐Christopher Keogh (ORCID: https://orcid.org/0000-0002-2219-8623)
- Yicheng Long (ORCID: https://orcid.org/0000-0003-3578-5197)
- Jeremy Chang (ORCID: https://orcid.org/0000-0002-2680-4934)
- Matthew R. Marunde (ORCID: https://orcid.org/0009-0007-5934-7200)
- Conrad Smith (ORCID: https://orcid.org/0009-0002-6853-5784)
- Shixin Liu (ORCID: https://orcid.org/0000-0003-4238-7066)
- Ari Melnick (ORCID: https://orcid.org/0000-0002-8074-2287)
- Rochelle M. Shih (ORCID: https://orcid.org/0000-0002-3218-4479)
- Arjun Ravishankar (ORCID: https://orcid.org/0000-0001-8366-4838)
- Alexia Martínez de Paz (ORCID: https://orcid.org/0000-0003-0808-1389)
- Andrew W. Daman (ORCID: https://orcid.org/0000-0001-8144-0574)
- Steven Z. Josefowicz (ORCID: https://orcid.org/0000-0001-7453-779X)
- Rachel Niec (ORCID: https://orcid.org/0000-0002-8525-3693)
- Michael J. Bale (ORCID: https://orcid.org/0000-0002-6899-1459)
- Mythili Ketavarapu (ORCID: https://orcid.org/0000-0003-1813-2813)
- John Cohen (ORCID: https://orcid.org/0000-0003-1772-8236)
- Leandro Cerchietti (ORCID: https://orcid.org/0000-0003-0608-1350)
- Michael Richard Green (ORCID: https://orcid.org/0000-0001-6309-9472)
- Alejandro Martin-Trujillo (ORCID: https://orcid.org/0000-0003-1089-3941)
- Dughan Ahimovic (ORCID: https://orcid.org/0000-0002-5849-335X)
- Joseph Chai-Yuen Sun (ORCID: https://orcid.org/0000-0001-8062-9033)
- Yuchen Sun (ORCID: https://orcid.org/0009-0008-8920-8575)
- Vipin Kumar (ORCID: https://orcid.org/0000-0002-2838-2472)
- Mark Owyong (ORCID: https://orcid.org/0000-0001-6731-2381)
- Christopher R. Chin (ORCID: https://orcid.org/0000-0002-2140-3197)
- Chenyang Jiang (ORCID: https://orcid.org/0000-0002-7851-6125)
- Christopher R. Flowers (ORCID: https://orcid.org/0000-0002-9524-3990)
- Christina S. Leslie (ORCID: https://orcid.org/0000-0002-4571-5910)
- Christopher E. Mason (ORCID: https://orcid.org/0000-0002-1850-1642)
- Rui Yang (ORCID: https://orcid.org/0000-0001-9358-9907)
- Wendy Béguelin (ORCID: https://orcid.org/0000-0002-4894-9229)
- Bria Graham (ORCID: https://orcid.org/0009-0005-8869-3036)
- Wilfred Wong (ORCID: https://orcid.org/0000-0003-1363-5235)
- Laiba F Khan (ORCID: https://orcid.org/0009-0000-5427-0653)
- Ioannis Karagianidis
Institutions
- Yale New Haven Hospital (US)
- Memorial Sloan Kettering Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Cornell University (US)
- Josep Carreras Leukaemia Research Institute (ES)
- EpiCypher (United States) (US)
- Weill Cornell Medicine (US)
- Rockefeller University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-11
- DOI
- https://doi.org/10.64898/2025.12.08.692984
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00