Differential oligomerization regulates PHF13 chromatin affinity and function.

PHF13 is a H3K4me3 epigenetic reader that modulates key chromatin processes including transcription, DNA damage response, and chromatin architecture. PHF13 is found aberrantly regulated in different cancers and its misexpression alters the epigenetic landscape of key transcription factors that regulate epithelial-to-mesenchymal transition. In this study, we sought to understand how PHF13's chromatin affinity and diverse chromatin functions are intrinsically regulated. Our results show that PHF13 can oligomerize via conserved ordered regions in its N- and C- terminus increasing its chromatin valence and avidity, promoting polymer-polymer phase separation (PPPS) and chromatin inaccessibility. Impressively, a ∼3- to 5-fold overexpression of PHF13 was sufficient to globally compact chromatin visible by optical microscopy, dependent on its ordered dimerizing regions and oligomerization potential. Unexpectedly, we discovered that PHF13 can self-associate independent of its ordered domains via intrinsically disordered regions, which conversely reduced PHF13's chromatin affinity, formed liquid-liquid phase separated (LLPS) condensates, and differentially impacted gene expression. Our findings support that there is an intrinsic balance between PHF13's ordered and disordered regions and that PHF13 can phase transition between polymer-polymer and liquid-liquid phase separation states to impact chromatin structure and function.