MLL3/MLL4 methyltransferase activities control early embryonic development and embryonic stem cell differentiation in a lineage-selective manner.

Autor: Xie G; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA., Lee JE; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA., Senft AD; The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Park YK; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA., Jang Y; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA., Chakraborty S; Unit on Genome Structure and Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Thompson JJ; Unit on Genome Structure and Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., McKernan K; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA., Liu C; Transgenic Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Macfarlan TS; The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Rocha PP; Unit on Genome Structure and Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.; National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Peng W; Departments of Physics and Anatomy and Cell Biology, The George Washington University, Washington, DC, USA., Ge K; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. kai.ge@nih.gov.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2023 Apr; Vol. 55 (4), pp. 693-705. Date of Electronic Publication: 2023 Apr 03.
DOI: 10.1038/s41588-023-01356-4
Abstrakt: H3K4me1 methyltransferases MLL3 (KMT2C) and MLL4 (KMT2D) are critical for enhancer activation, cell differentiation and development. However, roles of MLL3/4 enzymatic activities and MLL3/4-mediated enhancer H3K4me1 in these processes remain unclear. Here we report that constitutive elimination of both MLL3 and MLL4 enzymatic activities prevents initiation of gastrulation and leads to early embryonic lethality in mice. However, selective elimination of MLL3/4 enzymatic activities in embryonic, but not extraembryonic, lineages leaves gastrulation largely intact. Consistent with this, embryonic stem cells (ESCs) lacking MLL3/4 enzymatic activities can differentiate toward the three embryonic germ layers but show aberrant differentiation to extraembryonic endoderm (ExEn) and trophectoderm. The failure in ExEn differentiation can be attributed to markedly reduced enhancer-binding of the lineage-determining transcription factor GATA6. Furthermore, we show that MLL3/4-catalyzed H3K4me1 is largely dispensable for enhancer activation during ESC differentiation. Together, our findings suggest a lineage-selective, but enhancer activation-independent, role of MLL3/4 methyltransferase activities in early embryonic development and ESC differentiation.
(© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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