DOT1L-mediated H3K79me2 directs B-cell repertoire establishment, marginal zone development, and germinal center function

Abstract

Disruptor of telomeric silencing 1-like (DOT1L) is an epigenetic regulator that promotes gene expression by methylating lysine 79 on histone H3 and recruits transcription factors to gene targets. DOT1L is also an oncogenic driver in cancers that affect developing lymphocytes, yet how DOT1L activity regulates B-cell maturation remains poorly defined. Here, we use deep-sequencing and conditional knockout models to elucidate gene targets of H3K79me2, and the mechanistic contribution of DOT1L, during key stages of murine B-cell development. In the bone marrow, Dot1l was upregulated in pro B cells. Deep sequencing revealed that H3K79me2 accumulated during maturation. The genomic distribution of H..