A non-canonical monovalent zinc finger stabilizes the integration of Cfp1 into the H3K4 methyltransferase complex COMPASS

Abstract

COMPlex ASsociating with SET1 (COMPASS) is a histone H3 Lys-4 methyltransferase that typically marks the promoter region of actively transcribed genes. COMPASS is a multi-subunit complex in which the catalytic unit, SET1, is required for H3K4 methylation. An important subunit known to regulate SET1 methyltransferase activity is the CxxC zinc finger protein 1 (Cfp1). Cfp1 binds to COMPASS and is critical to maintain high level of H3K4me3 in cells but the mechanisms underlying its stimulatory activity is poorly understood. In this study, we show that Cfp1 only modestly activates COMPASS methyltransferase activity in vitro. Binding of Cfp1 to COMPASS is in part mediated by a new type of monovalent zinc finger (ZnF). This ZnF interacts with the COMPASS’s subunits RbBP5 and disruption of this interaction blunts its methyltransferase activity in cells and in vivo. Collectively, our studies reveal that a novel form of ZnF on Cfp1 enables its integration into COMPASS and contributes to epigenetic signaling.

DIM5/KMT1 controls fungal insect pathogenicity and genome stability by methylation of histone H3K4, H3K9 and H3K36

“…Unlike H3K9me, H3K4me is related exclusively to actively transcribed genes [2,16], and catalyzed by the H3K4 methylase COMPASS (COMplex of Proteins Associated with SET1), which comprises SET1/KMT2 and other components in Saccharomyces cerevisiae [17]. SET1/KMT2catalyzed H3K4me is often associated with the early transcribed regions of active genes [18][19][20][21], and regulated by CxxC zinc finger protein 1 (Cfp1) binding the COMPASS [22]. H3K4me depends on the activity of COMPASS binding mono-ubiquitinated histone H2B and free nucleosome with its catalytic module [23], and can define the transcriptional status of a genomic region and protect the genome from the replication stress and instability induced by transcription-replication conflicts in S. cerevisiae [24].…”

Analyzing the impact of CFP1 mutational landscape on epigenetic signaling

“…50 Consistently, in vitro studies show that CPS40 moderately activates COMPASS methyltransferase activity for peptides that are either non-, mono-, or dimethylated on H3K4, leading to a cumulative ~3.6-fold loss in the k cat of COMPASS for the formation of H3K4me3. 10 Conversely, the absence of CPS40 renders COMPASS nearly inactive in vitro when using chromatin ubiquitinated on histone H2B as the substrate. 51 This observation is intriguing as CPS40, which docks on the top of COMPASS and makes contact with RbBP5 36 and the nucleosome core particle DNA, 51 makes little to no contact with the ubiquitin moiety.…”

Sharing Marks: H3K4 Methylation and H2B Ubiquitination as Features of Meiotic Recombination and Transcription

“…Besides participating in leukemia, MLL1/MLL2 are indispensable in embryogenesis [130]. A Set1/COMPASS subunit required for H3K4me3 possesses the CXXC zinc finger protein 1 (CXXC1 or Cfp1, a Spp1 yeast ortholog), which binds to unmethylated CpG islands [150]. CXXC1 has been described as having a pivotal function in oocyte development [151].…”