TIF1β regulates the pluripotency of embryonic stem cells in a phosphorylation-dependent manner

Abstract

Transcription networks composed of various transcriptional factors specifically expressed in undifferentiated embryonic stem (ES) cells have been implicated in the regulation of pluripotency in ES cells. However, the molecular mechanisms responsible for self-renewal, maintenance of pluripotency, and lineage specification during differentiation of ES cells are still unclear. The results of this study demonstrate that a phosphorylation-dependent chromatin relaxation factor, transcriptional intermediary factor–1β (TIF1β), is a unique regulator of the pluripotency of ES cells and regulates Oct3/4–dependent transcription in a phosphorylation-dependent manner. TIF1β is specifically phosphorylated in pluripotent mouse ES cells at the C-terminal serine 824, which has been previously shown to induce chromatin relaxation. Phosphorylated TIF1β is partially colocalized at the activated chromatin markers, and forms a complex with the pluripotency-specific transcription factor Oct3/4 and subunits of the switching defective/sucrose nonfermenting, ATP-dependent chromatin remodeling complex, Smarcad1, Brg-1, and BAF155, all of which are components of an ES-specific chromatin remodeling complex, esBAF. Phosphorylated TIF1β specifically induces ES cell–specific genes and enables prolonged main-tenance of an undifferentiated state in mouse ES cells. Moreover, TIF1β regulates the reprogramming process of somatic cells in a phosphorylation-dependent manner. Our results suggest that TIF1β provides a phosphorylation-dependent, bidirectional platform for specific transcriptional factors and chromatin remodeling enzymes that regulate the cell differentiation process and the pluripotency of stem cells.

Zinc Finger Protein ZFP57 Requires Its Co-factor to Recruit DNA Methyltransferases and Maintains DNA Methylation Imprint in Embryonic Stem Cells via Its Transcriptional Repression Domain

“…KAP1 has been shown to be important for the maintenance and differentiation of embryonic stem cells (53,56,57). In addition, DNA methylation genomic imprint is maintained in ES cells, and de novo methylation is established during ES cell differentiation (58).…”

Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements

“…Trim28 knockout is embryonic lethal, and a maternal allele deletion leads to epigenetic instability during the mouse oocyte to embryo transition (Cammas et al 2000;Messerschmidt et al 2012). In murine embryonic stem cells, this protein is important for self-renewal (Hu et al 2009;Seki et al 2010). TRIM28 is also essential for the silencing of endogenous and some exogenous retroviruses in murine embryonic cells Goff 2007, 2009;Matsui et al 2010;Rowe et al 2010), where its KRAB-ZFP-mediated docking triggers the formation of heterochromatin, notably through the recruitment of SETDB1, the histone methyltransferase responsible for depositing the H3K9me3 repressive mark (Schultz et al 2002;Ivanov et al 2007;Frietze et al 2010), and of DNA methyltransferases, the action of which extends to adjacent CpG islands (Quenneville et al 2011(Quenneville et al , 2012Zuo et al 2012).…”

Erase–Maintain–Establish: Natural Reprogramming of the Mammalian Epigenome

“…2;Satou 2001;Li et al 2003;Satou et al 2004;Wang et al 2005Wang et al , 2007Jin et al 2007;Tsuruma et al 2007;Kamitani et al 2008Kamitani et al , 2011Peng et al 2009;Seki et al 2010;Liang et al 2011;Maruyama et al 2011;Huang et al 2013). For most of these, the KRAB-ZFPs included, TRIM28 functions as a co-repressor down-regulating gene transcription by its heterochromatin-inducing activity at its target sites (Iyengar and Farnham 2011;Cheng 2014).…”

“…Additional insights to TRIM28 function in vivo were gained from studies in preimplantation embryos (Satou 2001;Li et al 2003;Satou et al 2004;Wang et al 2005Wang et al , 2007Jin et al 2007;Tsuruma et al 2007;Kamitani et al 2008Kamitani et al , 2011Peng et al 2009;Seki et al 2010;Liang et al 2011;Maruyama et al 2011;Huang et al 2013). TRIM28 attracts chromatin writers and readers (right) (Nielsen et al 1999;Ryan et al 1999;Schultz et al 2001Schultz et al , 2002Quenneville et al 2011;Zuo et al 2012).…”