SETD7 Regulates the Differentiation of Human Embryonic Stem Cells

Abstract

The successful use of specialized cells in regenerative medicine requires an optimization in the differentiation protocols that are currently used. Understanding the molecular events that take place during the differentiation of human pluripotent cells is essential for the improvement of these protocols and the generation of high quality differentiated cells. In an effort to understand the molecular mechanisms that govern differentiation we identify the methyltransferase SETD7 as highly induced during the differentiation of human embryonic stem cells and differentially expressed between induced pluripotent cells and somatic cells. Knock-down of SETD7 causes differentiation defects in human embryonic stem cell including delay in both the silencing of pluripotency-related genes and the induction of differentiation genes. We show that SETD7 methylates linker histone H1 in vitro causing conformational changes in H1. These effects correlate with a decrease in the recruitment of H1 to the pluripotency genes OCT4 and NANOG during differentiation in the SETD7 knock down that might affect the proper silencing of these genes during differentiation.

Critical roles of protein methyltransferases and demethylases in the regulation of embryonic stem cell fate

“…Consistent with these findings, Babaie et al reported upregulation of SETD7 in hESCs after knockdown of OCT4, supporting intricate roles of these factors as it pertains to ESC pluripotency 48 . Additional evidence further supports SETD7 involvement in hESCs differentiation, as SETD7 knockdown impedes silencing of pluripotent markers and delays differentiation 49 . These findings support that SETD7 is upregulated during cell differentiation 45,47,49,50 .…”

“…Additional evidence further supports SETD7 involvement in hESCs differentiation, as SETD7 knockdown impedes silencing of pluripotent markers and delays differentiation 49 . These findings support that SETD7 is upregulated during cell differentiation 45,47,49,50 . Accordingly, increased Setd7 levels during mESC differentiation mediate Setd7-dependent H3K4me1 to regulate genes associated with differentiation and induce smooth muscle-associated genes 47 .…”

Set7 mediated interactions regulate transcriptional networks in embryonic stem cells

“…In contrast to other histone modifiers, the expression of Set7 is significantly up-regulated in Sca1+ cells as well as embryoid bodies, myoblast and human ESC differentiation (29,40,41). While these results suggest that Set7 has a role in differentiation we still do not know the regulatory machineries and epigenetic determinants that segregate and define different cell fates.…”

miR‐372 and miR‐373 enhance the stemness of colorectal cancer cells by repressing differentiation signaling pathways

“…Among them, VDR is the nuclear receptor of 1,25dihydroxyvitamin D3, which has been reported to induce differentiation of testicular germ cells and T cells (Blomberg Jensen et al, 2012;Zhou et al, 2017). SETD7 is a lysine methyltransferase that mediates the methylation of proteins and is induced during the differentiation of human ESCs (Castano et al, 2016). SPOP, an E3 ubiquitin ligase adaptor, mediates the ubiquitination and degradation of Gli2 and inhibits Hedgehog signaling, which affects cell differentiation (Zhang et al, 2009).…”

“…Quantitative RT-PCR analysis revealed that miR-372/373 downregulated the mRNA expression of these genes (Figs 3D and S3B), indicating a strong inhibitory effect. We then focused on and further investigated the protein levels of three new target genes, VDR, SETD7 and SPOP, all of which are involved in cell differentiation (Blomberg Jensen et al, 2012;Castano et al, 2016;Zhang et al, 2009;Zhou et al, 2017). Western blot analysis revealed that overexpression of miR-372/373 inhibited the protein levels of all the targets in both HCT116 and RKO cells, with the exception of SETD7 in an assay with miR-372 in RKO cells (Fig.…”