Setd1b, encoding a histone 3 lysine 4 methyltransferase, is a maternal effect gene required for the oogenic gene expression program

Abstract

Germ cell development involves major reprogramming of the epigenome to prime the zygote for totipotency. Histone 3 lysine 4 (H3K4) methylations are universal epigenetic marks mediated in mammals by six H3K4 methyltransferases related to fly Trithorax, including two yeast Set1 orthologs: Setd1a and Setd1b. Whereas Setd1a plays no role in oogenesis, we report that Setd1b deficiency causes female sterility in mice. Oocyte-specific Gdf9-iCre conditional knockout (Setd1b Gdf9 cKO) ovaries develop through all stages; however, follicular loss accumulated with age and unfertilized metaphase II (MII) oocytes exhibited irregularities of the zona pellucida and meiotic spindle. Most Setd1b Gdf9 cKO zygotes remained in the pronuclear stage and displayed polyspermy in the perivitelline space. Expression profiling of Setd1bGdf9 cKO MII oocytes revealed (1) that Setd1b promotes the expression of the major oocyte transcription factors including Obox1, 2, 5, 7, Meis2 and Sall4; and (2) twice as many mRNAs were upregulated than downregulated, suggesting that Setd1b also promotes the expression of negative regulators of oocyte development with multiple Zfp-KRAB factors implicated. Together, these findings indicate that Setd1b serves as maternal effect gene through regulation of the oocyte gene expression program.

The Trithorax group protein dMLL3/4 instructs the assembly of the zygotic genome at fertilization

“…The fact that dMLL3/4 is dispensable for morphologically normal oogenesis contrasts with previous observations for other SET domain histone methyltransferases across different species [19][20][21][22]. The fact that dMLL3/4 is dispensable for morphologically normal oogenesis contrasts with previous observations for other SET domain histone methyltransferases across different species [19][20][21][22].…”

DNMT1 modulates interneuron morphology by regulatingPak6expression through crosstalk with histone modifications

“…Consistent with changes in H3K4me3 levels, we found an elevated expression of components facilitating H3K4 trimethylation upon Dnmt1 deletion by screening the RNA sequencing dataset published in Pensold et al, 2016 [29]. This included transcripts coding for the histone-lysine-N-methyltransferases (HKMT) KMT2D and KMT2G (SETD1B), which specifically perform mono-and tri-methylation at H3K4 [58][59][60]. Hence, altered expression of HKMT like KMT2D or KMT2G may facilitate DNA methylation-independent alterations in gene transcription in POA-derived Dnmt1-deficient interneurons.…”

“…Dnmt1deficient embryonic POA-interneurons displayed transcriptional changes of diverse genes involved in the trimethylation of H3K4, which is associated to permissive chromatin structure. In detail, an increased expression of Kmt2d and Kmt2g coding for histone-lysine N-methyltransferases (HMT [58][59][60]) was observed in embryonic FACSenriched Hmx3-Cre/tdTomato/Dnmt1 loxP 2 cells (Supp. Figure 1).…”

SET domain containing 1B gene is mutated in primary hepatic neuroendocrine tumors

“…SETD1B , encoding a histone 3 lysine 4 methyltransferase, is a component of the SET1 complex ( SET1C )/COMPASS complex that participates in many life processes, such as the oncogenic gene expression program and Spemann's organizer gene activation in Xenopus . SETD1B is a maternal effect gene required for the oogenic gene expression program and a novel recurrently mutated gene in chronic myeloid leukemia . SETD1B is essential for hematopoietic stem and progenitor cell homeostasis in adult mice .…”