The molecular logic of Nanog-induced self-renewal in mouse embryonic stem cells

• Published in: Nature communications Vol. 10; no. 1; p. 1109
• Main Authors: Heurtier, Victor, Owens, Nick, Gonzalez, Inma, Mueller, Florian, Proux, Caroline, Mornico, Damien, Clerc, Philippe, Dubois, Agnes, Navarro, Pablo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.03.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/32; 38; 38/91; 42; 42/100; 45; 45/15; 631/208/176/2016; 631/337/100; 631/337/572; 631/532/2117; Animals; Biochemistry, Molecular Biology; Cell Line; Cell Self Renewal - genetics; Cell Self Renewal - physiology; Cell self-renewal; Cellular Biology; Chromatin; Development Biology; Embryo cells; Embryology and Organogenesis; Enhancer Elements, Genetic; Enhancers; Gene expression; Gene Expression Regulation; Gene regulation; Gene Regulatory Networks; Genomics; Histone Code - genetics; Humanities and Social Sciences; Leukemia Inhibitory Factor - genetics; Leukemia Inhibitory Factor - metabolism; Life Sciences; Mice; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; multidisciplinary; Nanog Homeobox Protein - genetics; Nanog Homeobox Protein - metabolism; Otx Transcription Factors - genetics; Otx Transcription Factors - metabolism; Otx2 protein; Pluripotency; Science; Science (multidisciplinary); Signal transduction; Stem cell transplantation; Stem cells; Subcellular Processes; Transcription factors
• DOI: 10.1038/s41467-019-09041-z
• ISSN: 2041-1723

Transcription factor networks, together with histone modifications and signalling pathways, underlie the establishment and maintenance of gene regulatory architectures associated with the molecular identity of each cell type. However, how master transcription factors individually impact the epigenomic landscape and orchestrate the behaviour of regulatory networks under different environmental constraints is only partially understood. Here, we show that the transcription factor Nanog deploys multiple distinct mechanisms to enhance embryonic stem cell self-renewal. In the presence of LIF, which fosters self-renewal, Nanog rewires the pluripotency network by promoting chromatin accessibility and binding of other pluripotency factors to thousands of enhancers. In the absence of LIF, Nanog blocks differentiation by sustaining H3K27me3, a repressive histone mark, at developmental regulators. Among those, we show that the repression of Otx2 plays a preponderant role. Our results underscore the versatility of master transcription factors, such as Nanog, to globally influence gene regulation during developmental processes. Transcription factor (TF) networks are essential for the molecular identity of each cell type. Here, the authors show that TF Nanog utilises multiple molecular strategies to enhance embryonic stem cell self-renewal, which include regulation of chromatin accessibility in the presence of LIF or maintenance of H3K27me3 at developmental regulators in its absence.