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Haoyi WANG, Ph. D.

Genome Engineering; Genome and Epigenome Editing.

Staff: Wang Haoyi, Liu Xiaojuan, Liu Xiang, Feng Wanyou
Postdoc: Rehan Sadiq Shaikh
Students:AnChenrui, Liu Lei, Xiang Guanghai, Cheng Chen, Liu Xiaoyi, Zhang Xingying, Zhang Yongping, Yang Peng, Zhang Tongtong, Cao Shiwei, Song Yanze, Cao Yuanwei, Li Jiaxin, Xue Xutong

• WANG Group website

  Current Research and Future Directions

  1. CRISPR and TALEN-mediated genome editing across the mammalian epigenetic and genetic landscape

  Despite the power of TALEN and CRISPR technologies, it is known that the efficiency of genome editing using site-specific nucleases can vary widely depending on genomic region. This is thought to result from the combined effects of differing genetic composition and epigenetic state for each particular locus. We propose to systematically characterize the efficiency of TALEN and CRISPR/Cas-mediated genome editing across major epigenetic marks and genetic composition, to gain mechanistic insights about the variation. Using all the experimental data, we will develop a comprehensive computational model to describe the variability in efficiency for TALEN and CRISPR/Cas genome editing in relation to the epigenetic status and genetic composition of target genomic loci.

  2. Establishment of highly efficient genome editing platform for therapeutic applications.

  To restore the gene function in genetic diseases, traditional gene therapy uses integrating vectors to insertthe wild type gene copy randomly into the genome of patient cells. The integration of viral vectors can potentially induce insertional mutagenesis and toxicity. In addition, expressing the transgene from exogenous locus will likely fail to achieve the physiological expression level, and could be subjected to epigenetic silencing. The significant development of programmable site-specific DNA endonucleases, including ZFNs, TALENs and the CRISPR system,makes endogenous gene correction a possible strategy for curing genetic disease. We want to achieve high efficiency gene correction in disease relevant cell types directly, to establish therapeutic methods for genetic disorders. Since Sickle Cell Disease (SCD) and β-Thalassemia, two of the most common genetic diseases, are both due to mutations within HBB gene, our initial aim is to achieve efficient correction of mutations within HBB gene in the CD34+ HSCs from Sickle Cell Disease and β-Thalassemia patients.

  3. Develop novel technologies for site-specific editing of the epigenetic modification. In addition to using genome editing to change the DNA sequence, we are also working on developing methods to modify the epigenetic status of specific genomic locus. We are interested in changing the status of DNA methylation as well as histone modification. Using these tools, we will be able to study the relationship between epigenetic status and gene expression, and develop novel disease model and therapeutic methods.



ZEN (zygote electroporation of nuclease) enables high throughput genome editing mice



The Casilio system for gene regulation, epigenetic editing and chromosomal labeling


Mutiplexed Genome Editing in ES Cells and Mouse using CRISPR/Cas 

Plain english:
  Genome engineering technologies are invaluable tools for understanding the function of genes in development disease. In recent years, the programmable site-specific DNA endonucleases, including zinc finger nucleases (ZFNs), transcription activator–like effector nucleases (TALENs) and the clustered, regularly interspaced short palindromic–repeat (CRISPR) system, have gained tremendous popularity and become widely used for genome engineering in cell lines and animal species ranging from Drosophila to primates. In addition to continually improving TALEN and CRISPR technologies, the Wang lab will focus on developing novel technologies to achieve more efficient and specific genome and epigenome editing. We will focus our research in the following two directions:
  1. Characterize and improve the TALEN and CRISPR systems to achieve higher efficiency and specificity
  2. Establish and optimize genome editing technology in hematopoietic stem cells and T lymphocytes, develop novel therapeutic methods
  3. Develop technologies for regulation of endogenous gene expression and epigenetic modifications, establish disease model and therapeutic methods

 

Selected publications:
(*Co-first author, # Corresponding author)

  1. Cheng AW*#, Jillette N*, Lee P, Plaskon D, Fujiwara Y, Wang W, Taghbalout A, Wang H#. “Casilio: a versatile CRISPR-Cas9-Pumilio hybrid for gene regulation and genomic labeling.” Cell Research, 2016;26:254-257.
  2. Qin W, Kutny PM, Maser RS, Dion SL, Lamont JD, Zhang Y, Perry GA, Wang H#.“Generating Mouse Models Using CRISPR-Cas9 Mediated Genome Editing.” Current Protocols in Mouse Biology, 2016;6(1):39-66.
  3. Qin W, Dion SL, Kutny PM, Zhang Y, Cheng AW, Jillette NL, Malhotra A, Geurts AM, Chen YG, Wang H#. “Efficient CRISPR/Cas9-mediated genome editing in mice by zygote electroporation of nuclease.” Genetics, 2015;200(2):423-430.
  4. Wang H*, Yang H*, Shivalila CS*, Dawlaty MM, Cheng AW, Zhang F, Jaenisch R. “One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas mediated genome engineering.” Cell, 2013;153(4):910-8. 
  5. Yang H*, Wang H*, Shivalila CS*, Cheng AW, Shi L, Jaenisch R. “One-step generation of mice carrying reporter and conditional allele by CRISPR/Cas mediated genome editing” Cell, 201; 154(6), 1370-1379.
  6. Wang H*, Hu YC*, Markoulaki S, Welstead GG, Shivalila CS, Cheng AW, Pyntikova T, Dadon D, Voytas DF, Bogdanove AJ, Page DC, Jaenisch R. “TALEN-mediated editing of the Mouse Y Chromosome.” Nature Biotechnology, 2013;31(6):530-2.
  7. Cheng AW*, Wang H*, Yang H, Shi L, Katz Y, Rangarajan S, Theunissen TW, ShivalilaCS,Dadon DB, Jaenisch R. “Multiplexed activation of endogenous genes by CRISPR-on, a RNA-guided transcriptional activator system.” Cell Research, 2013; 23(10): 1163-1171.
  8. Maetzel D*,Sarkar S*, Wang H*, Mosleh LA, Cheng AW, Xu P, Gao Q, Mitalipova M, Jaenisch R. “Genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cells derived from Niemann-Pick Type C patient-specific iPS cells.” Stem Cell Reports, 2014;2(6):866-80.
  9. Theunissen T*, Powell B*, Wang H*, Mitalipova M, Faddah D, Reddy J, Fan Z, Maetzel D, Ganz K, Shi L, Lungjangwa T, Imsoonthornruksa S, Stelzer Y, Rangarajan S, D’Alessio A, Zhang J, Gao Q, Dawlaty M, Young R, Gray N, Jaenisch R. “Systematic Identification of Culture Conditions for Induction and Maintenance of Naive Human Pluripotency” Cell Stem Cell, 2014; pii: S1934-5909(14)00298-7.
  10. Yang H, Wang H, JaenischR. “Generating genetically modified mice using CRISPR/Cas-mediated genome engineering.” Nature protocols, 2014;9(8):1956-68.
  11. Li Y, Wang H, Muffat J, Cheng AW, OrlandoDA, Loven J, Rahl P, Kwok SM, Feldman DA, Bateup HS, Hockemeyer D, MitalipovaM, SabatiniBL, Sur M, YoungRA, Jaenisch R. “Global transcriptional repression in human Rett Syndrome neurons suggests therapeutic strategies.” Cell Stem Cell, 2013; 13(4):446-458.
  12. Faddah D, Wang H, Buganim Y, Cheng AW, Jaenisch R. “Expression of Nanog is biallelic and equally variable as other pluripotency factors.” Cell Stem Cell, 2013;13(1):23-9.


One-Step Generation of Mice Carrying Reporter and Conditional Alleles by CRISPR/Cas-Mediated Genome Engineering