Chromatin; DNA Damage; Genetics; Histones; Neural Crest; Stem Cells; Cellular Reprogramming
Stem Cell Center, Yale: Stem Cell Genetics
We focus on elucidating epigenetic mechanisms for mammalian stem cell biology, cellular reprogramming (iPS) and embryonic development, with an emphasis on chromatin biology. Maintenance of genome integrity is an important issue during embryonic development and our work discovered the first link between epigenetics and genomic stability in mammalian cells (Nature 2009 V457, 57-62). Our most recent research has revealed several unexpected functions of epigenetic factors in determining iPSC quality (Cell Stem Cell 2014, two in press), and controlling telomere length and the aging/senescence of pluripotent stem cells (Developmental Cell, 2014, 29(1) 7-19). These findings motivate us to investigate how epigenetic mechanisms control various DNA elements in mammalian genomes and how it is linked to the potency of stem cells. We are using biochemistry, cell biology, mouse genetics, and genomics approaches to address these questions.
Specialized Terms: Chromatin biology; Histone variants; Modifications and chromatin remodeling complexes; Cellular reprogramming (iPS) and stem cell biology; Mammalian neural crest cell; Mammalian DNA damage response
Extensive Research Description
Current research focuses on 1) Determining the role of H2A.X in differentiation and cellular reprogramming (iPS cells). H2A.X is a unique histone variant, which is highly enriched in ES cells. We are using genomic and biochemistry approach to investigate the function of H2A.X in transcriptional regulation and cell fate determination. 2) Delineating the pathways regulated by H2A.X and WSTF in embryonic development and its implication in human Williams syndrome. We are using mouse genetics approach to investigate their functions in pluripotent neural crest cells and tissue-specific stem cells. 3) Investigating the functions of H2A.X and WSTF in DNA repair pathways. We are focusing on identifying their functions in maintaining genome integrity and preventing aberrant transcription. We welcome young scientists with similar interests to join us to study these interesting and intriguing questions.
- Wu T, Stadtfeld M, Tseng Z, Liu Y, Tahmasian M, Hochedlinger K & Xiao A*. Histone Variant H2A.X-Mediated Epigenetic Mechanisms are Critical for Maintaining Genome Stability and Pluripotency in ES and iPS Cells. (2014) Cell Stem Cell in press
- Buganim Y., Markoulaki S.,*, Wietmarschen N., Hoke H., Wu T., Ganz K., Akhtar-Zaidi B., He Y., Abraha B., Porubsky D., Kulenkampff E., Faddah D., Shi L., Gao Q., Sarkar Q., Cohen M., Goldman J., Nery J., Schultz M.,. Ecker J., Xiao A., Young R., Lansdorp P. and Jaenisch R. The developmental potential of iPSCs is greatly influenced by the selection of the reprogramming factors. (2014) Cell Stem Cell in press
- Dai J., Liu Y., Na L., Chiourea M., Okuka M., Wu T, Chunlin M., Wang L, Wang L, Yin Y., Yuan J., Zuo B., Wang F., Ye X., Li Z, Pan X., Yin Z., Chen L., Keefe D.J., Gagos S., Xiao A.* and Liu L* Rif1 Maintains Telomere Length Homeostasis of Embryonic Stem Cells by Mediating Subtelomeric Heterochromatin Silencing. (2014) Developmental Cell 29(1) 7-19 PMID: 24735877
- Xiao A., Li H., Shechter D., Ahn S.H.,. Fabrizio L.A., Erdjument-Bromage H., Ishibe-Murakami S., Wang B., Tempst P., Hoffman K., Patel D.J., Elledge, S.J., and Allis C.D. (2009) WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity. Nature (research article) 457, 57-62 See news and view, Nature V458, 581
- Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity. Zhao X, Jankovic V, Gural A, Huang G, Pardanani A, Menendez S, Zhang J, Dunne R, Xiao A, Erdjument-Bromage H, Allis CD, Tempst P, Nimer SD. Genes Dev. 2008 Mar 1;22(5):640-53. doi: 10.1101/gad.1632608.
- Xiao A., Wu H., Louis D.N., Pandolfi P.P., and Van Dyke T.A. (2002) Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN Mutation. Cancer Cell 1: 157-66.