Signaling induced biophysical disruption of repressed chromatin domains drives immune cell fate

Alexia Martínez de Paz; Christopher R. Chin; Mythili Ketavarapu; Yuchen Sun; Matthew R. Marunde; Jeremy T.-H. Chang; Laiba F Khan; John Cohen; Rui Yang; Michael J. Bale; Andrew W. Daman; Vigneshwari E. Kumar; Chenyang Jiang; Dughan J. Ahimovic; Mark Owyong; Arjun Ravishankar; Wilfred Wong; Rochelle M. Shih; Bria Graham; Conrad Smith; Ioannis Karagianidis; Leandro C. A. Cerchietti; Christopher R. Flowers; Michael R. Green; Christopher E. Mason; Joseph Chai-Yuen Sun; Alejandro Martin-Trujillo; Rachel E. Niec; Yicheng Long; Michael‐Christopher Keogh

doi:10.64898/2025.12.08.692984

ImmunologybioRxivDec 11, 2025

Preprint

Signaling induced biophysical disruption of repressed chromatin domains drives immune cell fate

Alexia Martínez de Paz iD, Christopher R. Chin iD, Mythili Ketavarapu iD, Yuchen Sun iD, Matthew R. Marunde iD, Jeremy T.-H. Chang iD, Laiba F Khan iD, John Cohen iD, Rui Yang iD, Michael J. Bale iD, Andrew W. Daman iD, Vigneshwari E. Kumar, Chenyang Jiang iD, Dughan J. Ahimovic iD, Mark Owyong iD, Arjun Ravishankar iD, Wilfred Wong iD, Rochelle M. Shih iD, Bria Graham iD, Conrad Smith iD, Ioannis Karagianidis, Leandro C. A. Cerchietti iD, Christopher R. Flowers iD, Michael R. Green, Christopher E. Mason iD, , Steven Zvi Josefowicz iD

Abstract

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.

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