The Histone Acetyltransferase MOF Is a Key Regulator of the Embryonic Stem Cell Core Transcriptional Network

• Published in: Cell stem cell Vol. 11; no. 2; pp. 163 - 178
• Main Authors: Li, Xiangzhi, Li, Li, Pandey, Ruchi, Byun, Jung S., Gardner, Kevin, Qin, Zhaohui, Dou, Yali
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 03.08.2012; Cell Press
• Subjects: alkaline phosphatase; Animals; Biological and medical sciences; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; chromatin; embryonic stem cells; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; epigenetics; Fundamental and applied biological sciences. Psychology; gene overexpression; Gene Regulatory Networks; genes; Histone Acetyltransferases - deficiency; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; histones; loci; methylation; Mice; Mice, Knockout; Molecular and cellular biology; Molecular genetics; Oligonucleotide Array Sequence Analysis; phenotype; transcription (genetics); transcription factors; Transcription. Transcription factor. Splicing. Rna processing; transcriptome; Acyltransferases; Transcription; Enzyme; Embryonic cell; Transferases; Stem cell; Histone acetyltransferase
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2012.04.023

Pluripotent embryonic stem cells (ESCs) maintain self-renewal and the potential for rapid response to differentiation cues. Both ESC features are subject to epigenetic regulation. Here we show that the histone acetyltransferase Mof plays an essential role in the maintenance of ESC self-renewal and pluripotency. ESCs with Mof deletion lose characteristic morphology, alkaline phosphatase (AP) staining, and differentiation potential. They also have aberrant expression of the core transcription factors Nanog, Oct4, and Sox2. Importantly, the phenotypes of Mof null ESCs can be partially suppressed by Nanog overexpression, supporting the idea that Mof functions as an upstream regulator of Nanog in ESCs. Genome-wide ChIP-sequencing and transcriptome analyses further demonstrate that Mof is an integral component of the ESC core transcriptional network and that Mof primes genes for diverse developmental programs. Mof is also required for Wdr5 recruitment and H3K4 methylation at key regulatory loci, highlighting the complexity and interconnectivity of various chromatin regulators in ESCs. ► The histone acetyltransferase Mof is essential for ESC self-renewal ► Mof directly regulates the Nanog-mediated ESC core transcriptional network ► Overexpression of Nanog partially rescues Mof deletion phenotypes in ESCs ► Mof regulates Wdr5 recruitment and H3K4 methylation at important loci in ESCs Histone modifications are critical determinants for chromatin structure and gene regulation. Genome-wide analysis in ESCs demonstrates that the histone acetyltransferase Mof maintains self-renewal and primes genes for differentiation as an integral component of the ESC core transcriptional network.