Faculty

Hao Wu, Ph.D.

Associate Professor of Genetics

Department: Genetics

Graduate Group Affiliations

Contact information

527 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6145

Office: 215-573-9360

Email:
haowu2@pennmedicine.upenn.edu

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.

Links
Wu Lab Website
Penn Epigenetics Institute
Google Scholar

Permanent link

> Perelman School of Medicine > Faculty > Details

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

Julia Leu, Ph.D. (Research Associate Professor, 2022-)
Qi Qiu, Ph.D. (Research Associate, 2018-)
Dongming Liang (Research Specialist, 2022-)
Hongjie Zhang, Ph.D. (Postdoctoral Fellow, 2022-)
Fan Li, Ph.D. (Postdoctoral Fellow, 2023-)
Ying Li (Visiting Scholar, 2023-)
Partita Mishra (Undergraduate, 2021-)
Saurav Nagpal (Undergraduate, 2023-)

Alumni

Xiangjin Kang, Ph.D. (Visiting Scholar, 2017-2018)
Abigail Byrne (Research Specialist, 2017-2018)
Wenchao Qian (Summer Research Intern, Tsinghua Univ, 2016)
Peng Hu, Ph.D. (Postdoctoral Fellow, 2016-2021)
Emily Fabyanic (Graduate Student, Pharmacology, 2017-2021)
Alex Wei (Graduate Student, Neuroscience, 2017-2022)
Jennifer Flournoy (Research Specialist, 2018-2020)

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

Wei A, Zhang H, Qiu Q, Fabyanic E, Hu P, Wu H: 5-hydroxymethylcytosines regulate gene expression as a passive DNA demethylation resisting epigenetic mark in proliferative somatic cells. bioRxiv 2023.

Alex Wei, Hao Wu : Mammalian DNA methylome dynamics: mechanisms, functions and new frontiers. Development (invited review) 149(24): doi: 10.1242/dev.182683. Epub, December 2022.

Zhou Y, Su Y, Li S, Kennedy BC, Zhang DY, Bond AM, Sun Y, Jacob F, Lu L, Hu P, Viaene AN, Helbig I, Kessler SK, Lucas T, Salinas RD, Gu X, Chen HI, Wu H, Kleinman JE, Hyde TM, Nauen DW, Weinberger DR, Ming GL, Song H. : Molecular landscapes of human hippocampal immature neurons across lifespan. Nature 607: 527–533, July 2022 Notes: https://doi.org/10.1038/s41586-022-04912-w In this collaborative study with the Song lab, we performed the single-nucleus RNA-seq (sNucDrop-seq) analysis of adult human cortical and hippocampal tissues.

Chen C, Yu W, Alikarami F, Qiu Q, Chen C, Flournoy J, Gao P, Uzun Y, Fang L, Davenport JW, Hu Y, Zhu Q, Wang K, Libbrecht C, Felmeister A, Rozich I, Ding Y, Hunger SP, Felix CA, Wu H, Brown PA, Guest EM, Barrett DM, Bernt KM, Tan K: Single-cell multiomics reveals increased plasticity, resistant populations and stem-cell-like blasts in KMT2A-rearranged leukemia. Blood 139(14): 2198-2211, April 2022 Notes: doi: 10.1182/blood.2021013442 In this collaborative study with the Tan lab at CHOP, we performed the single-cell DNA methylome analysis of human infant acute lymphoblastic leukemia (ALL).

Kwon DY, Xu B, Hu P, Zhao Y, Beagan JA, Nofziger JH, Cui Y, Phillips-Cremins JE, Blendy JA, Wu H, Zhou Z: Neuronal Yin Yang1 in the prefrontal cortex regulates transcriptional and behavioral responses to chronic stress in mice. Nature Communications 13(55), Jan 2022 Notes: Online only. https://doi.org/10.1038/s41467-021-27571-3 In this collaborative study with the Zhou lab, we performed the single-nucleus RNA-seq (sNucDrop-seq) analysis of a mouse model of chronic unpredictable stress.

Fabyanic EB*, Hu P*, Qiu Q, Wang T, Berrios KN, Flournoy J, Connolly DR, Zhou Z, Kohli RM, Wu H†: Quantitative single cell 5hmC sequencing reveals non-canonical gene regulation by non-CG hydroxymethylation. bioRxiv Mar 2021 Notes: Online only. We have combined bisulfite-based 5hmC chemical protection with A3A enzymatic deamination of 5mC and developed the first single-cell quantitative 5hmC sequencing method (snhmC-seq).

Uzun Y, Wu H, Tan K: Predictive modeling of single-cell DNA methylome data enhances integration with transcriptome data. Genome Research 31(1): 101-109, Jan 2021 Notes: doi: 10.1101/gr.267047.120.

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.

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.

Wang T, Luo M, Berrios KN, Schutsky EK, Wu H† Kohli RM† (†, co-corresponding): Bisulfite-free sequencing of 5-hydroxymethylcytosine with APOBEC-coupled epigenetic sequencing (ACE-Seq). Methods in Molecular Biology 2198: 349-367, Aug 2020.