CFP1-mediated H3K4me3 broad domains control early B cell lineage fate determination [RNA-Seq]

Histone H3K4me3 broad domain (BD) is a unique epigenetic feature to mark cell identity-associated genes, but its physiological role in lineage differentiation remains unclear. Here we show that CFP1, an integral component of the Setd1A/B methyltransferase complex, is critically required for functional H3K4me3-BD installation and B cell fate determination. Cfp1 deletion impairs H3K4me3-BDs on a subset of B-lineage genes and redistributes H3K4me3 from active genes to bivalent promoters. Transcription of subsets of H3K4me3-BD-bound gene is diminished in part due to reduced RNA Pol II at the promoter and gene body. Specifically, CFP1 ablation abolishes H3K4me3-BD at the recombination center and distal PAIR elements in the immunoglobulin heavy chain (IgH) gene, severely compromises its locus contraction for efficient V-to-DJ recombination and consequently arrests cells at the pro-B stage. Moreover, Cfp1-deficient pro-B cells upregulate a panel of progenitor and myeloid-specific genes with elevated H3K4me3 marks and can trans-differentiate into various myeloid cell types. Therefore, our study reveals pivotal roles for CFP1-mediated H3K4me3-BDs in the transcriptional regulation of cell lineage fate specification and commitment.