Owyong, M. | Search bioRxiv

bioRxiv2025

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.

immunology↗

bioRxiv2023

Early antigen receptor signaling in natural killer cells alters STAT4-dependent fate decisions via epigenetic remodeling

Lymphocyte differentiation depends on activation via antigen and cytokines during the immune response to infection. How the timing and integration of these signals program the epigenetic and functional fate of these cells is not completely understood. In this study, we find that interleukin (IL)-12 signaling received by innate and adaptive lymphocytes has a context-dependent role for immune memory formation. In the absence of a preceding and/or sufficient antigen receptor signaling event, IL-12 impairs the adaptive expansion of cytotoxic lymphocytes. In contrast, sufficient antigen-receptor signaling redirects inflammatory cytokine signals to promote memory differentiation via cooperation of STAT4 and AP-1 transcription factors. By this crucial epigenetic mechanism, optimally equipped lymphocytes are selected for memory formation rather than a terminal effector cell fate. Whereas T cells are hardwired to be shielded from premature IL-12 signaling, NK cells rely on coincidental early antigen receptor signaling for adaptive responses. Together, step-wise integration of antigen and cytokine signaling optimizes both effector and memory differentiation, allowing for promiscuous recruitment into the acute immune response while promoting avidity maturation in memory populations of both innate and adaptive lymphocytes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/565992v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@192b969org.highwire.dtl.DTLVardef@1cabd1aorg.highwire.dtl.DTLVardef@145139aorg.highwire.dtl.DTLVardef@9faae_HPS_FORMAT_FIGEXP M_FIG C_FIG Key points- Adaptive NK cell responses rely on sequential integration of antigen and inflammatory signals. - Epigenetic redirection of STAT4 genomic binding promotes adaptive programming. - CD8+ T cell fate depends on antigen-dependent integration of inflammatory signaling. - STAT/AP-1 cooperation underlies step-wise integration of antigen and cytokine signaling in NK cells and CD8+ T cells.

immunology↗