SPOC1 (PHF13) is a Molecular Reader and Effector of H3K4me2/3

SPOC1 is a chromatin affiliated protein with a functional role in stem cell differentiation, cell division, DNA damage response and higher order chromatin organization. To gain insight into SPOC1’s ability to modulate these processes, we elucidated the mechanisms targeting SPOC1 to chromatin and its genome wide localization. Our results demonstrate that SPOC1 binds chromatin in a multivalent fashion via its PHD domain and a centrally located domain, which interact with H3K4me2/3 and DNA, respectively. Consistently, the 3-dimensial structure of SPOC1’s PHD domain in complex with an H3K4me3 peptide could be solved. ChIP sequencing of SPOC1 in murine ES cells revealed an extensive co-occurrence with H3K4me2/3, DNAse hypersensitivity sites and Polycomb at key metabolic, cell cycle and developmental targets. Furthermore RNA sequencing demonstrated that a substantial fraction of these targets were either up or down regulated after SPOC1 depletion. Together these data identify SPOC1 as a bona fide H3K4me2/3 molecular reader and transcriptional regulator of diverse chromatin functions.