Faculty

Kavitha Sarma, Ph.D.

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Wistar Institute Assistant Professor of Cell and Developmental Biology
Department: Cell and Developmental Biology
Graduate Group Affiliations

Contact information
3601 Spruce St. Rm 234
Philadelphia, PA
Lab: 215-898-3970
Education:
Ph.D. (Biochemistry)
Rutgers University, 2007.
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Description of Research Expertise

Research Interests: RNA interactions in epigenetic gene regulation and genome organization.


Keywords: epigenetics, chromatin, polycomb, genome organization, non-coding RNA

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.

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?


Figure. R-loop structure and formation
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.



Lab Personnel:
Anna Bieluszewska Ph.D. - Postdoctoral Fellow
Emanuel Forciniti M.S. - Graduate Student
Skye Jacobson B.S. - Research Assistant I
Kelvin Okpokpo M.S. - Graduate Student
Nathaniel Rell B.S. - Research Assistant I
Phillip Wulfridge Ph.D. - NRSA Postdoctoral Fellow

Alumni:
Nicole Medeiros - Research Assistant III
Devinne Miller - Undergraduate Researcher
Joyce Bian - Undergraduate Researcher
Wenqing Ren- Postdoctoral Fellow Current Affiliation - Associate Researcher, Tongji University, China
Qingqing Yan Ph.D. - Postdoctoral Fellow Current Affiliation - Associate Researcher, Beijing China
Johnny Doherty B.S. - Research Assistant II Current Affiliation - Graduate student UPenn

Rotations:
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.

Selected Publications

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.

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.

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.

Wulfridge P and Sarma K: A nuclease- and bisulfite-based strategy captures strand-specific R-loops genome-wide. eLife Feb 2021.

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.

Qingqing Yan, Emily J. Shields, Roberto Bonasio, Kavitha Sarma: Mapping native R-loops genome-wide using a targeted nuclease approach. Cell Reports Oct 2019.

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.

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.

Simon Matthew D, Pinter Stefan F, Fang Rui, Sarma Kavitha, Rutenberg-Schoenberg Michael, Bowman Sarah K, Kesner Barry A, Maier Verena K, Kingston Robert E, Lee Jeannie T: High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation. Nature 504(7480): 465-9, Dec 2013.

Sarma Kavitha, Levasseur Pierre, Aristarkhov Alexander, Lee Jeannie T: Locked nucleic acids (LNAs) reveal sequence requirements and kinetics of Xist RNA localization to the X chromosome. Proceedings of the National Academy of Sciences of the United States of America 107(51): 22196-201, Dec 2010.

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Last updated: 12/02/2022
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