TY - JOUR TI - Impact of Sustained Transforming Growth Factor-β Receptor Inhibition on Chromatin Accessibility and Gene Expression in Cultured Human Endometrial MSC AU - Lucciola, Raffaella AU - Vrljicak, Pavle AU - Gurung, Shanti AU - Filby, Caitlin AU - Darzi, Saeedeh AU - Muter, Joanne AU - Ott, Sascha AU - Brosens, Jan J. AU - Gargett, Caroline E. T2 - Frontiers in Cell and Developmental Biology AB - Endometrial mesenchymal stem cells (eMSC) drive the extraordinary regenerative capacity of the human endometrium. Clinical application of eMSC for therapeutic purposes is hampered by spontaneous differentiation and cellular senescence upon large-scale expansion in vitro. A83-01, a selective transforming growth factor-β receptor (TGFβ-R) inhibitor, promotes expansion of eMSC in culture by blocking differentiation and senescence, but the underlying mechanisms are incompletely understood. In this study, we combined RNA-seq and ATAC-seq to study the impact of sustained TGFβ-R inhibition on gene expression and chromatin architecture of eMSC. Treatment of primary eMSC with A83-01 for 5 weeks resulted in differential expression of 1,463 genes. Gene ontology analysis showed enrichment of genes implicated in cell growth whereas extracellular matrix genes and genes involved in cell fate commitment were downregulated. ATAC-seq analysis demonstrated that sustained TGFβ-R inhibition results in opening and closure of 3,555 and 2,412 chromatin loci, respectively. Motif analysis revealed marked enrichment of retinoic acid receptor (RAR) binding sites, which was paralleled by the induction of RARB, encoding retinoic acid receptor beta (RARβ). Selective RARβ inhibition attenuated proliferation and clonogenicity of A83-01 treated eMSC. Taken together, our study provides new insights into the gene networks and genome-wide chromatin changes that underpin maintenance of an undifferentiated phenotype of eMSC in prolonged culture. DA - 2020/// PY - 2020 DO - 10.3389/fcell.2020.567610 DP - Frontiers VL - 8 J2 - Front. Cell Dev. Biol. LA - English SN - 2296-634X UR - https://www.frontiersin.org/articles/10.3389/fcell.2020.567610/full?utm_source=FRN&utm_medium=EMAIL_IRIS&utm_campaign=EMI_FRN_ARTICLEPUBLISHED_FOLLOWERS&utm_content=Twitter_1 Y2 - 2020/09/02/22:18:38 KW - Chromatin KW - Endometrium KW - Gene Regulatory Networks KW - Retinoic acid receptor beta KW - Transforming Growth Factor Receptor beta KW - human KW - mesenchymal stem cell ER -