SMYD2 Drives Mesendodermal Differentiation of Human Embryonic Stem Cells Through Mediating the Transcriptional Activation of Key Mesendodermal Genes

Abstract

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

Characterizing the Role of SMYD2 in Mammalian Embryogenesis—Future Directions

“…Activation of WNT signaling drives pluripotent stem cell commitment to mesendoderm lineages [40] and is the first step in the differentiation of human pluripotent stem cells (hPSC) to cardiomyocytes in vitro [27,42]. In addition to direct activation of β-Catenin, SMYD2-knockout hPSC lines demonstrated a remarkable reduction of H3K4me1 and H3K36me2 levels at the transcriptional start sites of several signature mesendoderm genes (T, EOMES, MIXL1, and GSC) during differentiation to mesoderm and endoderm [30]. Therefore, we hypothesize that the principal role of SMYD2 in heart development occurs prior to Nkx2.5 expression, which begins 3-4 days after WNT activation via β-Catenin translocation [43].…”

The Lysine Methyltransferase SMYD2 Is Required for Definite Hematopoietic Stem Cell Production in the Mouse Embryo

“…Members of the SMYD family are expressed prior to cellular differentiation during preimplantation development [12]; SMYD2 is expressed at the initial transition from the maternal to zygotic program at the 2-4 cell stage [13]. Recently, Bai et al [14] observed that SMYD2 expression during embryo development was significantly enhanced during mesendodermal, Vet. Sci.…”

“…Members of the SMYD family are expressed prior to cellular differentiation during preimplantation development [ 12 ]; SMYD2 is expressed at the initial transition from the maternal to zygotic program at the 2–4 cell stage [ 13 ]. Recently, Bai et al [ 14 ] observed that SMYD2 expression during embryo development was significantly enhanced during mesendodermal, pre-endoderm, and mesoderm cells, but not in neuroectodermal differentiation of human embryonic stem (ES) cells. SMYD2 activated transcription factors required for mesendodermal commitment via epigenetic promotion of H3 methylation near their corresponding transcriptional start sites [ 14 ].…”

“…Recently, Bai et al [ 14 ] observed that SMYD2 expression during embryo development was significantly enhanced during mesendodermal, pre-endoderm, and mesoderm cells, but not in neuroectodermal differentiation of human embryonic stem (ES) cells. SMYD2 activated transcription factors required for mesendodermal commitment via epigenetic promotion of H3 methylation near their corresponding transcriptional start sites [ 14 ].…”

A preview of selected articles

“…In our second Featured Article published this month in STEM CELLS Translational Medicine , Li et al describe how transfection with microencapsulated‐modified‐brachyury mRNA can induce MSCs to adopt a cardiopoietic fate that promotes enhanced cardioreparative activity 11 . In a Related Article published recently in STEM CELLS , Bai et al reported how a histone lysine methyltransferase regulates the differentiation of human embryonic stem cells (ESCs) by binding to and altering the chromatin landscape at the regulatory regions of crucial mesendodermal transcription factor genes, including brachyury 12 …”