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A Step Towards the Epigenetic Understanding of Early Human Development

Review of “SMYD2 Drives Mesendodermal Differentiation of Human Embryonic Stem Cells Through Mediating the Transcriptional Activation of Key Mesendodermal Genes” from STEM CELLS by Stuart P. Atkinson

The directed differentiation of human embryonic stem cells (hESCs) serves as a useful means of understanding early human development. As an example, the differentiation of hESCs into endoderm and mesoderm involves an intermediate state, mesendoderm, that displays equivalence with the primitive streak during gastrulation in early embryo development [1]. Therefore, the analysis of this hESC-derived cell type may allow us to begin to decipher the molecular pathways controlling development without raising ethical concerns.

Recently, researchers from the laboratory of Juang-Tian Yang (University of Chinese Academy of Sciences, Shanghai, China) set out to employ an hESC-based approach to understand the epigenetic control of mesendodermal commitment. Reporting in STEM CELLS [2], Bai et al. now report that the SET and MYND domain-containing protein 2 (SMYD2), a histone 3 lysine 36 dimethylase [3], controls the expression of critical mesendodermal genes by promoting the appearance of specific histone modifications at gene regulatory regions. Overall, this fascinating new study highlights the importance of epigenetic modifications to hESC early lineage commitment and perhaps early human development.

The authors first discovered low SMYD2 expression in hESCs; however, following induction of mesendodermal differentiation through a previously reported monolayer differentiation protocol [4], the expression of SMYD2 significantly increased. Of note, elevated SYMD2 expression did not occur during neuroectodermal differentiation of hESCs. To further explore the association of SMYD2 expression and mesendodermal differentiation, the team generated SMYD2 knockout hESCs. Analysis of these cells revealed that while hESCs retained their normal self-renewal ability and the ability to differentiate towards early neuroectoderm, they lost their ability to differentiate towards the mesendodermal lineage. 

Chromatin binding experiments then established that SMYD2 binds to the promoter regions of critical mesendodermal transcription factor genes, such as brachyury (T), eomesodermin (EOMES), mix paired‐like homeobox (MIXL1), and goosecoid homeobox (GSC), to promote their expression. The loss of SMYD2 reduced the levels of the expression of these genes, as expected, and this occurred alongside a reduction in the methylation of histone 3 lysine 4 (H3K4me1) and lysine 36 (H3K36me2), but not at histone 4 lysine 20 (H4K20me1), at the promoter regions of mesendodermal genes and at the global scale.

Overall, this fascinating new study suggests the general importance of SMYD2‐mediated H3K4me1 and H3K36me2 for the mesendodermal differentiation of hESCs, and in doing so, provides new insight into the function and mechanism of histone methyltransferases in the early lineage commitment of hESCs and, perhaps, early human development.

For more on how histone methylation can influence the differentiation of hESCs, and provide clues regarding the molecular mechanisms controlling early human development, stay tuned to the Stem Cells Portal!


  1. Tam PPL and Behringer RR, Mouse gastrulation: the formation of a mammalian body plan. Mechanisms of Development 1997;68:3-25.
  2. Bai H-J, Zhang P, Ma L, et al., SMYD2 Drives Mesendodermal Differentiation of Human Embryonic Stem Cells Through Mediating the Transcriptional Activation of Key Mesendodermal Genes. STEM CELLS 2019;37:1401-1415.
  3. Brown MA, Sims RJ, Gottlieb PD, et al., Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex. Molecular Cancer 2006;5:26.
  4. Vallier L, Touboul T, Brown S, et al., Signaling Pathways Controlling Pluripotency and Early Cell Fate Decisions of Human Induced Pluripotent Stem Cells. STEM CELLS 2009;27:2655-2666.