Embryonic stem cells (ESCs) are pluripotent cells derived from the inner cell mass of the blastocyst-stage embryo. They can be used as a model system to study the molecular basis of pluripotency and fate-specification during early mammalian development. They can also be used to derive various types of cells for disease modeling, drug discovery, and the development of cell-based therapies. However, the success of these studies and applications critically depends on the understanding of the mechanisms that control ESC self-renewal and differentiation. To systematically study ESC self-renewal, we have previously carried out a genome-wide siRNA screen in mouse ESCs and successfully identified a list of novel genes that are important self-renewal. We are currently investigating the function of several of these novel genes in ESCs with biochemical, genetic, and genomic approaches. For example, we have shown that the Ccr4-Not complex is required for both mouse and human ES cell self-renewal by inhibiting differentiation. The Fip1 gene regulates mRNA alternative polyadenylation to promote ESC self-renewal. The THO protein complex regulates pluripotency gene mRNA export and controls both ESC self-renewal and somatic cell reprogramming. The INO80 protein complex facilitates pluripotency gene activation in embryonic stem cell self-renewal, reprogramming, and blastocyst development. We are now using biochemical and genetic experiments to further study the function of these genes in ESCs, induced pluripotent stem cells, and mouse embryogenesis. Using similar approaches, we are also investigating the roles of other novel self-renewal regulators. Besides the characterization of the above self-renewal factors, we are collaborating with other laboratories to develop approaches to probe and identify environmental factors that may affect human development. We are using human ESCs as an in vitro model to study the developmental toxicity of the environmental compounds, and we hope to gain a better understanding on the impact of environmental factors on human embryogenesis and embryonic development. Finally, we will continue to use functional genetic approaches to study the guided-differentiation of ESCs and the self-renewal of other types of stem cells. We also plan to study the expression and the roles of stem cell genes in cancer. We hope that our studies will facilitate the development of stem cell therapies, and identify novel therapeutic targets or diagnostic markers for cancer treatment. In summary, we use ESCs as a model system to investigate the mechanism of stem cell self-renewal and differentiation. Our studies will lead to a better understanding of developmental biology, and it will contribute to the advance of the therapeutic use of stem cells in regenerative medicine, as well as the use of stem cells in the study of environmental sciences.

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U.S. National Inst of Environ Hlth Scis
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Brumbaugh, Justin; Di Stefano, Bruno; Wang, Xiuye et al. (2018) Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling. Cell 172:106-120.e21
Zhou, Bingying; Liu, Junwei; Ren, Zongna et al. (2017) Cnot3 enhances human embryonic cardiomyocyte proliferation by promoting cell cycle inhibitor mRNA degradation. Sci Rep 7:1500
Li, Pishun; Wang, Li; Bennett, Brian D et al. (2017) Rif1 promotes a repressive chromatin state to safeguard against endogenous retrovirus activation. Nucleic Acids Res 45:12723-12738
Zhang, S; Zhou, B; Wang, L et al. (2017) INO80 is required for oncogenic transcription and tumor growth in non-small cell lung cancer. Oncogene 36:1430-1439
Chen, Qing; Hu, Guang (2017) Post-transcriptional regulation of the pluripotent state. Curr Opin Genet Dev 46:15-23
Borkent, Marti; Bennett, Brian D; Lackford, Brad et al. (2016) A Serial shRNA Screen for Roadblocks to Reprogramming Identifies the Protein Modifier SUMO2. Stem Cell Reports 6:704-716
Zheng, Xiaofeng; Yang, Pengyi; Lackford, Brad et al. (2016) CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State. Stem Cell Reports 7:897-910
Wang, Li; Hu, Guang (2016) Remodeling super-enhancers and oncogenic transcription. Cell Cycle :1-2
Zhou, Bingying; Wang, Li; Zhang, Shu et al. (2016) INO80 governs superenhancer-mediated oncogenic transcription and tumor growth in melanoma. Genes Dev 30:1440-53
Bunch, Heeyoun; Lawney, Brian P; Burkholder, Adam et al. (2016) RNA polymerase II promoter-proximal pausing in mammalian long non-coding genes. Genomics 108:64-77

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