Proximity-dependent biotin identification (BioID) reveals a dynamic LSD1-CoREST interactome during embryonic stem cell differentiation

Lysine specific demethylase 1 (LSD1/KDM1A) regulates gene expression as part of the CoREST complex, along with co-repressor of REST (CoREST) and histone deacetylase 1 (HDAC1). CoREST is recruited to specific genomic loci by components of the core complex and numerous transient interactions with chromatin associated factors and transcription factors. To sample the chromatin environment in proximity to CoREST, we performed proximity-dependent biotin-identification (BioID) with four different members of the complex in 293T cells. Retaining only targets identified with 3 out of 4 baits, we identified 302 CoREST-associated proteins. Among this group were 16 of 18 known CoREST components and numerous novel associations, including readers (CHD3, 4, 6, 7 and 8), writers (KMT2B and KMT2D) and erasers (KDM2B) of histone methylation. However, components of other HDAC1 containing complexes (e.g. Sin3A, NuRD) were largely absent, suggesting that CoREST functions independently. As LSD1 plays an essential role in early embryonic development, we performed BioID using the endogeneously tagged protein in pluripotent, early- and late-differentiating embryonic stem cells. We identified 157 LSD1-associated proteins of which 66 were constitutively associated across all three time-points (44%), including novel interactions with the MMB and ChAHP complexes. These data imply that the majority of CoREST interactions are dynamic and highly cell type dependent.