The Wu lab is interested in understanding how epigenetic processes in multicellular organisms regulate gene expression to establish diverse cell types and to respond to changing environmental signals or metabolic states. We combine experimental approaches (biochemical, molecular, genetic, and genomic assays) with bioinformatics to study cell-type specification and maturation from mammalian stem cells (e.g. cardiovascular and neural lineages). We also start to study molecular mechanisms regulating the interaction between environment and epigenome and how extrinsic environmental signals regulate developmental processes or human pathologies through modifying epigenetic marks in the genome. Our long-term goal is to quantitatively analyze and engineer cell-type or environmental context specific epigenomes. Ultimately, we hope to use knowledge gained from epigenome analysis and engineering to inform therapeutic approaches to treat relevant human diseases.
Epigenomics, DNA methylation and demethylation, Transcriptional control, Single cell analysis, Stem cell biology, Neural and cardiac lineage specification and maturation, Interaction between environment and epigenome
DNA cytosine methylation (5-methylcytosine) is an evolutionarily conserved epigenetic mark and has a profound impact on transcription, development and genome stability. Historically, 5-methylcytosine (5mC) is considered as a highly stable chemical modification that is mainly required for long-term epigenetic memory. The recent discovery that ten-eleven translocation (TET) proteins can iteratively oxidize 5mC in the mammalian genome represents a paradigm shift in our understanding of how 5mC may be enzymatically reversed. It also raises the possibility that three oxidized 5mC bases generated by TET may act as a new class of epigenetic modifications.
Interestingly, key epigenetic enzymes such as TET family of DNA deoxygenate and JmjC-domain-containing histone demethylase directly utilize oxygen and some major metabolites as their cofactors to modify epigenetic marks on DNA or histone, supporting the notion that cells in multicellular organisms can rapidly adapt to changing environmental inputs or metabolic states by dynamically modifying their epigenome and gene expression programs.
Our laboratory uses high-throughput sequencing technologies, bioinformatics, mammalian genetic models, as well as synthetic biology tools to investigate the mechanisms by which proteins that write, read and erase DNA and histone modifications contribute to mammalian development and relevant human diseases. To achieve this goal, we are also interested in developing new genomic sequencing and programmable epigenome-modifying methods to precisely map and manipulate these DNA modifications in the complex mammalian genome.
Peng Hu, Ph.D. (Postdoctoral Fellow)
Emily Fabyanic (Graduate Student, Pharmacology)
Alex Wei (Graduate Student, Neuroscience)
Qi Qiu, Ph.D. (Postdoctoral Fellow)
Jennifer Flournoy (Research Specialist)
Xiangjin Kang, Ph.D. (Visiting Scholar, 2017-2018)
Abigail Byrne (Research Specialist, 2017-2018)
Wenchao Qian (Summer Research Intern, Tsinghua Univ, 2016)
1. Developing CRISPR/dCas9-based novel epigenome editing tools to dissect gene regulatory functions of epigenetic modifications in mammalian genomes.
2. Developing massively parallel single-cell epigenomic profiling methods to investigate the role of oxidized methylcytosines in developmental gene regulation and environment/epigenome interactions in vivo.
3. Developing and applying massively parallel single-cell/nucleus RNA-seq approach (e.g. Drop-seq & sNucDrop-seq) to dissect the cell-type composition and differentiation dynamics during mammalian cardiac and neural lineage specification and maturation.
Emily Schutsky, Jamie DeNizio, Peng Hu, Monica Yun Liu, Christopher Nabel, Emily Fabyanic, Young Hwang, Frederic Bushman, Hao Wu ǂ, Rahul Kohli ǂ (ǂ, co-corresponding): Nondestructive, base-resolution sequencing of 5-hydroxymethylcytosine using a DNA deaminase. Nature Biotechnology 2018 (In press).
Peng Hu*, Jian Liu*, Juanjuan Zhao*, Benjamin Wilkins, Katherine Lupino, Hao Wu ǂ, Liming Pei ǂ (ǂ, co-corresponding): Single-nucleus transcriptomic survey of cell diversity and functional maturation in the postnatal mammalian hearts. Genes & Development 2018 (in press).
Peng Hu*, Emily Fabyanic*, Deborah Y. Kwon, Sheng Tang, Zhaolan Zhou, Hao Wu: Dissecting Cell-Type Composition and Activity-Dependent Transcriptional State in Mammalian Brains by Massively Parallel Single-Nucleus RNA-Seq. Molecular Cell 68(5):1006-1015, Dec 2017.
Hao Wu, Xiaoji Wu, Yi Zhang: Base-resolution profiling of active DNA demethylation using MAB-seq and caMAB-seq. Nature Protocol 11(6): 1081-1100, Jun 2016.
Hao Wu, Yi Zhang: Charting oxidized methylcytosines at base resolution. Nature Structural & Molecular Biology 22(9): 656-661, Sep 2015.
Hao Wu, Yi Zhang: Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156(1-2): 45-68, Jan 2014.
Hao Wu*, Xiaoji Wu*, Li Shen, Yi Zhang: Single-base resolution analysis of active DNA demethylation using methylase-assisted bisulfite sequencing. Nature Biotechnology 32(12): 1231-1240, Dec 2014.
Soh Boon-Seng, Wu Hao, Chien Kenneth R: Cardiac regenerative medicine 2.0. Nature biotechnology 31(3): 209-11, Mar 2013.
Shen Li*, Wu Hao*, Diep Dinh, Yamaguchi Shinpei, D'Alessio Ana C, Fung Ho-Lim, Zhang Kun, Zhang Yi: Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics. Cell 153(3): 692-706, Apr 2013.
Xu Huansheng, Yi B Alexander, Wu Hao, Bock Christoph, Gu Hongcang, Lui Kathy O, Park Joo-Hye C, Shao Ying, Riley Alyssa K, Domian Ibrahim J, Hu Erding, Willette Robert, Lepore John, Meissner Alexander, Wang Zhong, Chien Kenneth R: Highly efficient derivation of ventricular cardiomyocytes from induced pluripotent stem cells with a distinct epigenetic signature. Cell research 22(1): 142-54, Jan 2012.
Wu Hao, Zhang Yi: Early embryos reprogram DNA methylation in two steps. Cell stem cell 10(5): 487-9, May 2012.
Tao Jifang*, Wu Hao*, Lin Quan, Wei Weizheng, Lu Xiao-Hong, Cantle Jeffrey P, Ao Yan, Olsen Richard W, Yang X William, Mody Istvan, Sofroniew Michael V, Sun Yi E: Deletion of astroglial Dicer causes non-cell-autonomous neuronal dysfunction and degeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 31(22): 8306-19, Jun 2011.
Wu Hao, Zhang Yi: Tet1 and 5-hydroxymethylation: a genome-wide view in mouse embryonic stem cells. Cell cycle (Georgetown, Tex.) 10(15): 2428-36, Aug 2011.
Wu Hao, Zhang Yi: Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes & development 25(23): 2436-52, Dec 2011.
Wu Hao, D'Alessio Ana C, Ito Shinsuke, Xia Kai, Wang Zhibin, Cui Kairong, Zhao Keji, Sun Yi Eve, Zhang Yi: Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473(7347): 389-93, May 2011.
Wu Hao, D'Alessio Ana C, Ito Shinsuke, Wang Zhibin, Cui Kairong, Zhao Keji, Sun Yi Eve, Zhang Yi: Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes & development 25(7): 679-84, Apr 2011.
Wu Hao, Tao Jifang, Chen Pauline J, Shahab Atif, Ge Weihong, Hart Ronald P, Ruan Xiaoan, Ruan Yijun, Sun Yi E: Genome-wide analysis reveals methyl-CpG-binding protein 2-dependent regulation of microRNAs in a mouse model of Rett syndrome. Proceedings of the National Academy of Sciences of the United States of America 107(42): 18161-6, Oct 2010.
Wu Hao, Coskun Volkan, Tao Jifang, Xie Wei, Ge Weihong, Yoshikawa Kazuaki, Li En, Zhang Yi, Sun Yi Eve: Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science (New York, N.Y.) 329(5990): 444-8, Jul 2010.
Wu Hao, Xu Jun, Pang Zhiping P, Ge Weihong, Kim Kevin J, Blanchi Bruno, Chen Caifu, Südhof Thomas C, Sun Yi E: Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines. Proceedings of the National Academy of Sciences of the United States of America 104(34): 13821-6, Aug 2007.
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Last updated: 08/16/2018
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