Kmt2b conveys monovalent and bivalent H3K4me3 in mouse spermatogonial stem cells at germline and embryonic promoters

Abstract

The mammalian male germline is sustained by a pool of spermatogonial stem cells (SSCs) that can transmit both genetic and epigenetic information to offspring. However, the mechanisms underlying epigenetic transmission remain unclear. The histone methyltransferase Kmt2b is highly expressed in SSCs and is required for the SSC-to-progenitor transition. At the stem-cell stage, Kmt2b catalyzes H3K4me3 at bivalent H3K27me3-marked promoters as well as at promoters of a new class of genes lacking H3K27me3, which we call monovalent. Monovalent genes are mainly activated in late spermatogenesis, whereas most bivalent genes are mainly not expressed until embryonic development. These data suggest that SSCs are epigenetically primed by Kmt2b in two distinguishable ways for the upregulation of gene expression both during the spermatogenic program and through the male germline into the embryo. Because Kmt2b is also the major H3K4 methyltransferase for bivalent promoters in embryonic stem cells, we also propose that Kmt2b has the capacity to prime stem cells epigenetically.

RETRACTED ARTICLE: m6A modification-mediated CBX8 induction regulates stemness and chemosensitivity of colon cancer via upregulation of LGR5

“…In our study, we discovered that CBX8 recruits KMT2b to the LGR5 promoter to maintain H3K4me3 modification status, implying that KMT2b potentially functions in tumorigenesis and tumor progression. Moreover, in stem cells, the classic function of KMT2b is to attach H3K4me3 to bivalent promoters with the aid of PRC1 component [15]; Interestingly, we found that the promoter of LGR5 which accumulated H3K4me3 and H3K27me3 was bivalent promoter. In addition, CBX8 is also a component of PRC1 complex.…”

“…Recent studies have reported that CBX proteins function in cooperation with other proteins to promote epigenetic activation or silencing of gene expression [13, 14]. As Set1/Trithorax-type H3K4 methyltransferases catalyze H3K4 methylation [15], we utilized an RNA interference (RNAi) screening approach to identify potential H3K4 modifiers responsible for LGR5 regulation. Notably, depletion of KMT2b, but not other enzymes, decreased LGR5 expression (Fig.…”

“…KMT2b encodes a ubiquitously expressed lysine methyltransferase specifically responsible for the deposition of H3K4me3 at gene promoters [15, 30], which is required for embryonic stem cell development [15] and neuronal differentiation [31]. However, the role of KMT2b in cancers has rarely been documented.…”

Tsga8 is required for spermatid morphogenesis and male fertility in mice

“…To identify a novel factor involved in spermatogenesis, we focused on the genes targeted by KMT2B and upregulated during spermiogenesis (Tomizawa et al, 2018). To this end, we reanalyzed data previously obtained from cultured germline stem cells (GSCs) with chromatin immunoprecipitation followed by sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) (Tomizawa et al, 2018).…”

“…Because the testis is the organ that expresses the largest number of genes of all organs in mice (Kimmins and Sassone-Corsi, 2005;Xia et al, 2020), the roles of the vast majority of the genes expressed during spermiogenesis for morphological remodeling remain unknown. We recently showed that a small subset of genes that are upregulated during spermiogenesis are potentially programmed for expression in undifferentiated spermatogonia by histone H3 lysine 4 trimethylation (H3K4me3) (Tomizawa et al, 2018). Chromatin priming and later activation is a phenomenon suggested in other systems such as pluripotent stem cells and macrophages (Glass and Natoli, 2016;Harikumar and Meshorer, 2015).…”