MMTR/Dmap1 Sets the Stage for Early Lineage Commitment of Embryonic Stem Cells by Crosstalk with PcG Proteins.

Dae Hyun Ha,Insung Na,Chang Su Lim,Jinseon Jeon,Chul Geun Kim,Young Jin Lee,Vladimir N Uversky,Su Youne Han,Si Woo Lee,Min Young Kim,Na Rae Jung,Sangwon Lee,Byung-Rok Do,Seung Han Son

doi:10.3390/cells9051190

Abstract

Chromatin remodeling, including histone modification, chromatin (un)folding, and nucleosome remodeling, is a significant transcriptional regulation mechanism. By these epigenetic modifications, transcription factors and their regulators are recruited to the promoters of target genes, and thus gene expression is controlled through either transcriptional activation or repression. The Mat1-mediated transcriptional repressor (MMTR)/DNA methyltransferase 1 (DNMT1)-associated protein (Dmap1) is a transcription corepressor involved in chromatin remodeling, cell cycle regulation, DNA double-strand break repair, and tumor suppression. The Tip60-p400 complex proteins, including MMTR/Dmap1, interact with the oncogene Myc in embryonic stem cells (ESCs). These proteins interplay with the stem cell-related proteome networks and regulate gene expressions. However, the detailed mechanisms of their functions are unknown. Here, we show that MMTR/Dmap1, along with other Tip60-p400 complex proteins, bind the promoters of differentiation commitment genes in mouse ESCs. Hence, MMTR/Dmap1 controls gene expression alterations during differentiation. Furthermore, we propose a novel mechanism of MMTR/Dmap1 function in early stage lineage commitment of mouse ESCs by crosstalk with the polycomb group (PcG) proteins. The complex controls histone mark bivalency and transcriptional poising of commitment genes. Taken together, our comprehensive findings will help better understand the MMTR/Dmap1-mediated transcriptional regulation in ESCs and other cell types.

Highlights

Preimplantation embryo-derived embryonic stem cells (ESCs) are able to self-renew and differentiate into multi-lineage cell types in vitro and in vivo with a normal karyotype [1,2,3]
We found that the Mat1-mediated transcriptional repressor (MMTR)/Dmap1 occupancy to the promoter was not different between stemness and developmental genes and during differentiation (d0 versus d3), whereas the Suz12 occupancy showed an inverse correlation with the gene expression (Figure 5B)
We identified a novel mechanism of MMTR/Dmap1 in terms of bivalent regulations in maintenance and differentiation of mouse ESCs (mESCs)

Summary

Introduction

Preimplantation embryo-derived embryonic stem cells (ESCs) are able to self-renew and differentiate into multi-lineage cell types in vitro and in vivo with a normal karyotype [1,2,3]. To expand the range of cell types derived efficiently from the in vitro differentiation and thereby broaden the successful use of ESC-derived cells in medical applications, good understanding of the molecular mechanisms underlying self-renewal and pluripotency of ESCs is needed. This important research area is not fully elucidated yet.

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