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Research Interests: RNA interactions in epigenetic gene regulation and genome organization.
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Keywords: epigenetics, chromatin, polycomb, genome organization, non-coding RNA
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We are interested in understanding the molecular mechanisms of RNA mediated epigenetic gene regulation. Aberrations in epigenetic gene silencing can be a causal mechanism of numerous human disease and developmental syndromes. We use a combination of biochemical, cell biological and functional genomics approaches in embryonic stem cell, neural stem cell, and cancer cell models to elucidate the molecular mechanisms and functional implications of RNA containing chromatin structures in gene regulation and in genome organization.
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We are fascinated by triplex nucleic acid structures known as R-loops, that are comprised of a DNA:RNA hybrid and displaced ssDNA. R-loops are formed during transcription when the mRNA invades dsDNA (forming the DNA:RNA hybrid) and exposes a ssDNA that can then adopt a G quadruplex (G4) structure (Figure 4). Transcription from G rich repetitive regions results in the formation of G4 DNA that impedes the reannealing of DNA strands, promotes DNA:RNA hybridization, and stabilizes R-loops. In addition to known regulatory roles, R-loops are closely linked to increased DNA damage and genome instability. Stable aberrant R-loops have also been discovered in several neurological disorders, neurodegenerative diseases, and cancers. Discovering the genome-wide locations of R-loops is challenging because of the requirement for large sample size and inefficient enrichment using the monoclonal antibody that recognizes the RNA:DNA hybrid within R-loops. We have developed a new antibody independent approach, called MapR, to identify native R-loops genome-wide. Some questions that are interested in exploring are: Where do R-loops form in specific disease states? How do unscheduled R-loops contribute to neurodegenerative diseases and cancers? What are the protein factors that function in R-loop resolution and stabilization? How can R-loops impact gene regulation and genome organization in disease states?
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R-loop structure and formation. R-loops are triplex nucleic acid structures comprising an RNA-DNA hybrid and displaced ssDNA. They are formed during transcription when the mRNA invades the dsDNA (forming the RNA-DNA hybrid) and exposes an ssDNA that can adopt a G quadruplex (G4) structure. R-loops can also form when specific long non-coding RNAs associate with chromatin to regulate gene expression.
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Lab Personnel:
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Kuo-Chen (Jimmy) Fang - Research Assistant II
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Emanuel Forciniti M.S. - Graduate Student
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Michelle Lee Lynsey Ph.D. Postdoctoral Fellow
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Afrora Muca - Lab manager/Research Technician
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Shachinthaka Mudiyanselage - Postdoctoral Fellow
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Kelvin Okpokpo M.S. - Graduate Student
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Phillip Wulfridge Ph.D. - NRSA Postdoctoral Fellow
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Alumni:
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Nicole Medeiros - Research Assistant III Current Affiliation - Associate Scientist Janssen
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Devinne Miller - Undergraduate Researcher
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Joyce Bian - Undergraduate Researcher
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Wenqing Ren- Postdoctoral Fellow Current Affiliation - Associate Researcher, Tongji University, China
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Qingqing Yan Ph.D. - Postdoctoral Fellow Current Affiliation - Associate Researcher, Beijing China
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Johnny Doherty B.S. - Research Assistant II Current Affiliation - Graduate student UPenn
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Nathaniel Rell B.S. - Research Assistant II Current Affiliation - Research Assistant Drexel University
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Skye Jacobson B.S. - Research Assistant II Current Affiliation - Associate Scientist Janssen
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Anna Bieluszewska Ph.D. - Postdoctoral Fellow
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Rotations:
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Students who have been admitted to a graduate program at the University of Pennsylvania are encouraged to inquire about current rotation projects by sending an email to: ksarma@wistar.org.
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Selected Publications
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Wulfridge P and Sarma K : Intertwining roles of R-loops and G-quadruplexes in DNA repair, transcription, and genome organization. Nature Cell Biology July 2024.
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Wulfridge P, Yan Q, Rell N, Doherty J, Jacobson S, Offley S, Deliard S, Feng K, Phillips-Cremins JE, Gardini A, Sarma K: G-quadruplexes associated with R-loops promote CTCF binding. Molecular Cell Aug 2023.
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Yan Q*, Wulfridge P*, Doherty J, Fernandez-Luna JL, Real PJ, Tang HY, Sarma K. : Proximity labeling identifies a repertoire of site-specific R-loop modulators. Nature Communications Jan 2022.
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Bieluszewska A, Wulfridge P, Doherty J, Ren W, Sarma K. : ATRX histone binding and helicase activities have distinct roles in neuronal differentiation. Nucleic Acids Research Sept 2022.
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Shukla V*, Samaniego-Castruita D*, Dong Z, Gonzalez-Avalos E, Yuita H, Yan Q, Sarma K, Rao A: TET deficiency perturbs mature B cell homeostasis and promotes oncogenesis associated with accumulation of G-quadruplex and R-loop structures. Nature Immunology Jan 2022.
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Wulfridge P and Sarma K: A nuclease- and bisulfite-based strategy captures strand-specific R-loops genome-wide. eLife Feb 2021.
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Wenqing Ren*,Nicole Medeiros*, Robert Warneford-Thomson, Phillip Wulfridge, Qingqing Yan, Joyce Bian, Simone Sidoli, Benjamin A. Garcia, Emmanuel Skordalakes, Eric Joyce, Roberto Bonasio, Kavitha Sarma: Disruption of ATRX-RNA interactions uncovers roles in ATRX localization and PRC2 function. Nature Communications May 2020.
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Qingqing Yan, Emily J. Shields, Roberto Bonasio, Kavitha Sarma: Mapping native R-loops genome-wide using a targeted nuclease approach. Cell Reports Oct 2019.
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Sarma Kavitha, Cifuentes-Rojas Catherine, Ergun Ayla, Del Rosario Amanda, Jeon Yesu, White Forest, Sadreyev Ruslan, Lee Jeannie T: ATRX directs binding of PRC2 to Xist RNA and Polycomb targets. Cell 159(4): 869-83, Nov 2014.
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Cifuentes-Rojas Catherine, Hernandez Alfredo J, Sarma Kavitha, Lee Jeannie T: Regulatory interactions between RNA and polycomb repressive complex 2. Molecular cell 55(2): 171-85, Jul 2014.
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Last updated: 02/28/2025
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