Hao Wu, Ph.D.
Associate Professor of Genetics
Core member, Penn Epigenetics Institute
Member, Penn Institute of Regenerative Medicine (IRM)
Member, Penn Cardiovascular Institute (CVI)
Member, CHOP Center for Mitochondrial and Epigenomic Medicine (CMEM)
Department: Genetics
Graduate Group Affiliations
Contact information
527 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6145
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.
Permanent linkB.S. (Biological Sciences and Biotechnology)
Tsinghua University, 2002.
Ph.D. (Epigenetic regulation of neural stem cell differentiation)
University of California Los Angeles, 2009.
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 epigenomeDescription 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-)
William Gao (Graduate Student, GCB, MD/PhD program, 2023-)
Ying Li (Research Specialist, 2023-)
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)
Partita Mishra (Undergraduate, 2021-2023)
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
William Gao, Peng Hu, Qi Qiu, Xiangjin Kang, Kenneth C. Bedi, Kotaro Sasaki, Kenneth B. Margulies, Hao Wu: Integrated single-cell and spatial multiomic analysis reveals widespread reactivation of developmental programs in diseased human hearts. bioRxiv April 2025.Yu H, Nagi SS, Usoskin D, Hu Y, Kupari J, Bouchatta O, Yan H, Cranfill SL, Gautam M, Su Y, Lu Y, Wymer J, Glanz M, Albrecht P, Song H, Ming GL, Prouty S, Seykora J, Wu H, Ma M, Marshall A, Rice FL, Li M, Olausson H, Ernfors P, Luo W: Leveraging deep single-soma RNA sequencing to explore the neural basis of human somatosensation. Nature Neuroscience November 2024.
IGVF Consortium: Deciphering the impact of genomic variation on function. Nature September 2024.
Feierman ER, Louzon S, Prescott NA, Biaco T, Gao Q, Qiu Q, Choi K, Palozola KC, Voss AJ, Mehta SD, Quaye CN, Lynch KT, Fuccillo MV, Wu H, David Y, Korb E: Histone variant H2BE enhances chromatin accessibility in neurons to promote synaptic gene expression and long-term memory. Molecular Cell August 2024.
Song L, Li Q, Xia L, Sahay AE, Qiu Q, Li Y, Li H, Sasaki K, Susztak K, Wu H, Wan L.: Single-cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape. Nature Communications July 2024.
Dingwall HL, Tomizawa RR, Aharoni A, Hu P, Qiu Q, Kokalari B, Martinez SM, Donahue JC, Aldea D, Mendoza M, Glass IA; Birth Defects Research Laboratory (BDRL); Wu H, Kamberov YG.: Sweat gland development requires an eccrine dermal niche and couples two epidermal programs. Developmental Cell January 2024.
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 September 2023.
Fabyanic EB*, Hu P*, Qiu Q*, Berríos KN, Connolly DR, Wang T, Flournoy J, Zhou Z, Kohli RM, Wu H†.: Joint single-cell profiling resolves 5mC and 5hmC and reveals their distinct gene regulatory effects. Nature Biotechnology August 2023.
Hsu F, Wu Q, Fabyanic EB, Wei A, Wu H, Clark AT: TET1 facilitates specification of early human lineages including germ cells. iScience July 2023.
Wang T, Fowler JM, Liu L, Loo CE, Luo M, Schutsky EK, Berríos KN, DeNizio JE, Dvorak A, Downey N, Montermoso S, Pingul BY, Nasrallah M, Gosal WS, Wu H, Kohli RM: Direct enzymatic sequencing of 5-methylcytosine at single-base resolution. Nature Chemical Biology June 2023.