CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), University of Chinese Academy of Sciences (CAS), CAS, Shanghai, People's Republic of China.
CAS Key Laboratory of Computational Biology, Laboratory of Epigenome Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences (SIBS), University of Chinese Academy of Sciences (CAS), CAS, Shanghai, People's Republic of China.
Stem Cells. 2019 Nov;37(11):1401-1415. doi: 10.1002/stem.3068. Epub 2019 Aug 12.
Histone methyltransferases play a critical role in early human development, whereas their roles and precise mechanisms are less understood. SET and MYND domain-containing protein 2 (SMYD2) is a histone lysine methyltransferase induced during early differentiation of human embryonic stem cells (hESCs), but little is known about its function in undifferentiated hESCs and in their early lineage fate decision as well as underlying mechanisms. Here, we explored the role of SMYD2 in the self-renewal and mesendodermal lineage commitment of hESCs. We demonstrated that the expression of SMYD2 was significantly enhanced during mesendodermal but not neuroectodermal differentiation of hESCs. SMYD2 knockout (SMYD2 ) did not affect self-renewal and early neuroectodermal differentiation of hESCs, whereas it blocked the mesendodermal lineage commitment. This phenotype was rescued by reintroduction of SMYD2 into the SMYD2 hESCs. Mechanistically, the bindings of SMYD2 at the promoter regions of critical mesendodermal transcription factor genes, namely, brachyury (T), eomesodermin (EOMES), mix paired-like homeobox (MIXL1), and goosecoid homeobox (GSC) were significantly enhanced during mesendodermal differentiation of SMYD2 hESCs but totally suppressed in SMYD2 ones. Concomitantly, such a suppression was associated with the remarkable reduction of methylation at histone 3 lysine 4 and lysine 36 but not at histone 4 lysine 20 globally and specifically on the promoter regions of mesendodermal genes, namely, T, EOMES, MIXL1, and GSC. These results reveal that the histone methyltransferase SMYD2 is dispensable in the undifferentiated hESCs and the early neuroectodermal differentiation, but it promotes the mesendodermal differentiation of hESCs through the epigenetic control of critical genes to mesendodermal lineage commitment. Stem Cells 2019;37:1401-1415.
组蛋白甲基转移酶在人类早期发育中起着至关重要的作用，但其作用和确切机制尚不清楚。SET 和 MYND 结构域包含蛋白 2（SMYD2）是一种在人类胚胎干细胞（hESC）早期分化过程中诱导的组蛋白赖氨酸甲基转移酶，但对于其在未分化的 hESC 及其早期谱系命运决定中的功能以及潜在机制知之甚少。在这里，我们研究了 SMYD2 在 hESC 的自我更新和中胚层谱系决定中的作用。我们证明，SMYD2 的表达在 hESC 的中胚层但不是神经外胚层分化过程中显著增强。SMYD2 敲除（SMYD2 -/-）不影响 hESC 的自我更新和早期神经外胚层分化，但阻断了中胚层谱系决定。通过将 SMYD2 重新引入 SMYD2 hESC 中，这种表型得到了挽救。从机制上讲，SMYD2 在关键中胚层转录因子基因的启动子区域的结合，即 brachyury（T）、eomesodermin（EOMES）、mix 配对样同源盒（MIXL1）和 goosecoid 同源盒（GSC），在 SMYD2 hESC 的中胚层分化过程中显著增强，但在 SMYD2 中完全被抑制。同时，这种抑制与组蛋白 3 赖氨酸 4 和赖氨酸 36 的甲基化显著减少有关，但组蛋白 4 赖氨酸 20 的甲基化以及中胚层基因的启动子区域的甲基化没有减少，即 T、EOMES、MIXL1 和 GSC。这些结果表明，组蛋白甲基转移酶 SMYD2 在未分化的 hESC 和早期神经外胚层分化中是可有可无的，但它通过对关键基因的表观遗传控制促进 hESC 的中胚层分化，从而促进中胚层谱系决定。干细胞 2019；37:1401-1415。
