Faculty

Hao Wu, Ph.D.

faculty photo
Assistant Professor of Genetics
Department: Genetics

Contact information
527 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6145
Office: 215-573-9360
Education:
B.S. (Biological Sciences and Biotechnology)
Tsinghua University, 2002.
Ph.D. (Epigenetic regulation of neural stem cell differentiation)
University of California Los Angeles, 2009.
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Description of Research Expertise

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.

Key Words

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

Description of Research

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.

Lab members

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)

Alumni

Xiangjin Kang, Ph.D. (Visiting Scholar, 2017-2018)
Abigail Byrne (Research Specialist, 2017-2018)
Wenchao Qian (Summer Research Intern, Tsinghua Univ, 2016)

Current Projects

1. Development of high-precision single-cell epigenomic profiling methods to investigate the role of oxidized methylcytosines in neural development, neurodegeneration and environment/neural epigenome interactions.
2. Development of novel epigenome editing tools to dissect gene regulatory functions of epigenetic DNA modifications in mammalian genomes.
3. Development of massively parallel and time-resolved single-cell RNA sequencing methods to study RNA dynamics (biogenesis, processing and decay), fast-responding TF regulatory network and temporal cell state trajectory (metabolic RNA labeling based RNA velocity) at single-cell levels.
4. Application of single-nucleus multi-omics approach (e.g. sNucDrop-seq, snATAC-seq and single-cell DNA methylome) to characterize precise cell-type composition and functional state heterogeneity in directed differentiation of human pluripotent stem cells towards cardiac lineages as well as during in vivo cardiac development, maturation and aging.

Rotation Projects: Please contact Hao for more details.

Selected Publications

Ho Y*,†, Hu P*, Peel MT, Chen, S, Camara PG, Epstein DJ, Wu H†, Liebhaber SA (†, co-corresponding): Single-cell transcriptomic analysis of adult mouse pituitary reveals sexual dimorphism and physiologic demand-induced cellular plasticity. Protein & Cell 11: 565–583, Mar 2020. Notes: In this collaborative study with the Liebhaber lab, we performed the single-cell RNA-seq (Drop-seq) experiments and computational analysis of mouse anterior pituitary tissues. GitHub – https://github.com/wulabupenn/mPit.

Qiu Q*, Hu P*, Qiu X, Govek KW, Camara PG, Wu H†: Massively parallel and time-resolved RNA sequencing in single cells with scNT-Seq Nature Methods 17(10): 991-1001, Oct 2020. Notes: We developed the first high-throughput metabolic RNA labeling based single-cell RNA sequencing method, which enables massively parallel analysis of newly transcribed and pre-existing mRNAs from the same cell. GitHub – https://github.com/wulabupenn/scNT-seq.

Schutsky EK, DeNizio JE, Hu P, Liu MY, Nabel CS, Fabyanic EB, Hwang Y, Bushman FD, Wu H†, Kohli RM† (†, co-corresponding): Nondestructive, base-resolution sequencing of 5-hydroxymethylcytosine using a DNA deaminase. Nature Biotechnology 36: 1083–1090, Oct 2018. Notes: In this collaborative study, we leveraged human DNA deaminase APOBEC3A to develop the first all enzyme based, non-destructive whole-genome 5hmC single-base resolution sequencing method. The Wu lab has performed method development and computational analysis.

Hu P*, Liu J*, Zhao J*, Wilkins BJ, Lupino K, Wu H†, Pei L† (†, co-corresponding): Single-nucleus transcriptomic survey of cell diversity and functional maturation in the postnatal mammalian hearts. Genes & Development 32(19-20): 1344-1357, Oct 2018. Notes: In this collaborative study, the Wu lab has generated the first large-scale single-nucleus transcriptomic atlas of mammalian cardiac tissues using sNucDrop-seq developed in our lab. GitHub – https://github.com/wulabupenn/Hu_GenesDev_2018

Hu P*, Fabyanic EB*, Kwon DY, Tang S, Zhou Z, Wu H†: 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. Notes: The Wu lab has developed sNucDrop-seq, one of the first high-throughput droplet microfluidics based single-nucleus RNA-seq methods (e.g. DroNc-seq from Regev lab at Broad). GitHub – https://github.com/wulabupenn/Hu_MolCell_2017.

Wu H, Zhang Y†: Charting oxidized methylcytosines at base resolution. Nature Structural & Molecular Biology 22(9): 656-661, Sep 2015.

Wu H*, Wu X*, Zhang Y†: Base-resolution profiling of active DNA demethylation using MAB-seq and caMAB-seq. Nature Protocol 11(6): 1081-1100, Jun 2016.

Wu H, Zhang Y†: Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156(1-2): 45-68, Jan 2014.

Wu H*,†, Wu X*, Shen L, Zhang Y† (†, co-corresponding): Single-base resolution analysis of active DNA demethylation using methylase-assisted bisulfite sequencing. Nature Biotechnology 32(12): 1231-1240, Dec 2014.

Soh BS, Wu H, Chien KR†: Cardiac regenerative medicine 2.0. Nature Biotechnology 31(3): 209-11, Mar 2013.

Shen L*, Wu H*,†, Diep D, Yamaguchi S, D'Alessio AC, Fung HL, Zhang K, Zhang Y† (†, co-corresponding): Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics. Cell 153(3): 692-706, Apr 2013.

Xu H*, Yi BA*, Wu H, Bock C, Gu H, Lui KO, Park JH, Shao Y, Riley AK, Domian IJ, Hu E, Willette R, Lepore J, Meissner A, Wang Z, Chien KR†: 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 H, Zhang Y†: Early embryos reprogram DNA methylation in two steps. Cell Stem Cell 10(5): 487-9, May 2012.

Tao J*, Wu H*, Lin Q, Wei W, Lu XH, Cantle JP, Ao Y, Olsen RW, Yang XW, Mody I, Sofroniew MV, Sun YE†: 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 H, Zhang Y†: Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes & Development 25(23): 2436-52, Dec 2011.

Wu H*, D'Alessio AC*, Ito S, Xia K, Wang Z, Cui K, Zhao K, Sun YE, Zhang Y†: Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473(7347): 389-93, May 2011.

Wu H, D'Alessio AC, Ito S, Wang Z, Cui K, Zhao K, Sun YE, Zhang Y†: 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 H*,†, Tao J*, Chen PJ, Shahab A, Ge W, Hart RP, Ruan X, Ruan Y, Sun YE† (†, co-corresponding): 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 H†, Coskun V, Tao J, Xie W, Ge W, Yoshikawa K, Li E, Zhang Y, Sun YE† (†, co-corresponding): Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science 329(5990): 444-8, Jul 2010.

Wu H, Xu J, Pang ZP, Ge W, Kim KJ, Blanchi B, Chen C, Südhof TC, Sun YE†: 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: 07/27/2022
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