Kazrani, A. A. | bioRxiv Science

bioRxiv2023

BCL7 proteins, metazoan-specific subunits of the mammalian SWI/SNF complex, bind the nucleosome core particle

BCL7 proteins are among the most recently identified subunits of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex and are absent from the unicellular version of the complex. Mutations in BCL7 proteins are associated with different kind of cancers including blood malignancies. The information on the molecular function and on the structure of BCL7 proteins is to date very limited. Here we report that BCL7 proteins directly bind the nucleosome core particle (NCP) and free DNA with high affinity. We demonstrate that BCL7 proteins form defined complexes with the NCP and we identify the conserved N-terminal part of BCL7 proteins as sufficient to nucleosome binding. We further characterize the impact of BCL7 protein mutations reported in cancer patients on NCP binding and show that the R11S driver mutation reduces the affinity for the nucleosome. Our findings clarify the molecular function of BCL7 proteins and help rationalize the impact of cancer-associated mutations.

biochemistry↗

bioRxiv2021

Clustered PHD domains in mixed lineage leukaemia proteins are attracted by acetylation-rich active promoters and enhancers

Histone lysine-specfic methyltransferase 2 (KMT2A-D) proteins, alternatively called mixed lineage leukaemia (MLL1-4) proteins, mediate positive transcriptional memory. As the catalytic subunits of human COMPASS-like complexes, they methylate H3K4 at promoters and enhancers. KMT2A-D contain understudied highly conserved triplets and a quartet of plant homeodomains (PHDs). Here, we show that all clustered PHDs localise to the well-defined loci of H3K4me3 and H3 acetylation-rich active promoters and enhancers. Surprisingly, we observe little difference in binding pattern between PHDs from promoter-specific KMT2A-B and enhancer-specific KMT2C-D. Fusion of the KMT2A CXXC domain to the PHDs drastically enhances their preference for promoters over enhancers. Hence, the presence of CXXC domains in KMT2A-B, but not KMT2C-D, may explain the promoter/enhancer preferences of the full-length proteins. Importantly, targets of PHDs overlap with KMT2A targets and are enriched in genes involved in the cancer pathways. We also observe that PHDs of KMT2A-D are mutated in cancer, especially within conserved folding motifs (Cys4HisCys2Cys/His), which cause a domain loss-of-function. Taken together, our data suggests that PHDs of KMT2A-D guide the full-length proteins to active promoters and enhancers, and thus play a role in positive transcriptional memory. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/462366v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1d62842org.highwire.dtl.DTLVardef@ed1041org.highwire.dtl.DTLVardef@1c62b43org.highwire.dtl.DTLVardef@1426bcd_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗