Orateur
Description
Cellular identity is defined by the selective activation of lineage-specific gene programs and the robust silencing of inappropriate ones. While pioneering transcription factors (TFs) can override topological constraints to drive fate transitions, the structural mechanisms that maintain chromatin state stability to prevent malignant remodeling remain poorly defined. In B-cell malignancies, this stability is often compromised, frequently coinciding with the aberrant expression of lineage-inappropriate TFs and the subsequent rewiring of the 3D genome. Here, we investigate the interplay between TF-mediated plasticity and the role of Linker Histone H1 in stabilizing the B-cell cistrome.
Prior investigations utilizing the BLaER1 transdifferentiation model demonstrated that the pioneering factor CEBPA utilizes its intrinsically disordered region (IDR) to facilitate phase separation and the formation of higher-order chromatin hubs. These findings suggest that instructive TFs act as biophysical organizers that actively reshape the 3D genome. We now propose, however, that such plasticity is normally restrained by H1-mediated structural barriers.
Supporting this hypothesis, our recent CUT&Tag profiling of H1 in Diffuse Large B-cell Lymphoma (DLBCL) and K562 cell lines reveals a striking and non-canonical enrichment at ATAC-seq-positive active enhancers. This localization suggests that H1 is not merely a global repressor but serves as a localized regulator of enhancer activity. Given that H1 is frequently co-mutated with enhancer-modulating enzymes (p300, CBP, KMT2D) in DLBCL, we hypothesize that H1 loss lowers the threshold for chromatin rewiring. This permissive epigenetic state may facilitate the aberrant recruitment or activity of TFs at regulatory elements, contributing to the transcriptional instability and malignant plasticity characteristic of lymphoma. Together, these data suggest a framework where H1 acts as an essential guardian of identity by modulating the physical and biochemical accessibility of the active genome.