Stefan Bekiranov
Associate Professor of Biochemistry & Molecular Genetics
Ph.D., University of California, Santa Barbara
Physical Modeling of Oligonucleotide Array Hybridization

 

My laboratory develops and applies computational statistics methods to functional genomic data with a focus on epigenetic data. Epigenetics is the study of heritable phenotypic traits not coded in the primary DNA sequence, which can be modified by environmental factors and comprise a complex regulatory network that controls a number of processes on DNA including transcription, replication and repair. A central element of this control network is chemical groups (e.g., acetyl or methyl) that are added or removed from DNA and histones, which package DNA in a cell’s nucleus. Control of processes such as transcription is achieved by making DNA sequences available or unavailable for factors including General Transcription Factors and Pol II that initiate transcription as well as recruitment of factors that facilitate each stage of transcription (i.e., promotion, elongation, etc.). Similarly, accessibility of DNA regulates the binding of the Origin Recognition Complex and subsequent initiation of DNA replication. Epigenetic factors have been shown to play a fundamental role in regulating cell differentiation, and the dysregulation of epigenetic processes have been implicated in a number of diseases including cancer, diabetes, and neurological disorders.

We are interested in characterizing the complex epigenetic regulatory network of histone modifications and DNA methylation, which exhibits extensive cross-talk. We apply machine-learning methods including Multivariate Regression Splines (MARS) and Bayesian Networks (BN) to epigenomic data in order to uncover this network and understand how it regulates transcription and DNA replication. We analyze both publicly available data sets (e.g., epigenomic data generated by K. Zhao’s lab and the ENCODE, modENCODE and Epigenomics Mapping Consortia) as well as data generated by colleagues here at UVa. In our collaborations, we are studying (1) preinitiation complex (PIC) and transcription factor dynamics and their role in regulation of transcription level and precision (2) epigenomic regulation of the epithelial to mesenchymal transition—a model of how cells are reprogrammed during metastasis (3) origins of DNA replication in the human genome and the epigenetic factors that drive them (4) the role of histone deacetylaces including Sir2 in aging and (5) the impact of chemicals in our environment (e.g., Bisphenol A) on our epigenome and subsequent phenotypic outcomes. An exciting aspect of the collaborative environment at UVa is that we are able to experimentally test our predicted epigenetic regulatory network models at the biochemical and phenotypic level.


Selected References

Mesner LD, Valsakumar V, Karnani N, Dutta A, Hamlin JL, Bekiranov S. (2011) "Bubble-chip analysis of human origin distributions demonstrates on a genomic scale significant clustering into zones and significant association with transcription." Genome Res. Jan [Epub ahead of print] [PubMed]

Stolzenberg DS, Grant PA, Bekiranov S. (2010) "Epigenetic methodologies for behavioral scientists." Horm Behav. Oct [Epub ahead of print] [PubMed]

Poorey K, Sprouse RO, Wells MN, Viswanathan R, Bekiranov S, Auble DT. (2010) "RNA synthesis precision is regulated by preinitiation complex turnover." Genome Res. 20(12):1679-88. Epub 2010 Sep 20. [PubMed]

Xu X, Hoang S, Mayo MW, Bekiranov S. (2010) "Application of machine learning methods to histone methylation ChIP-Seq data reveals H4R3me2 globally represses gene expression." BMC Bioinformatics. Jul 11:396. [PubMed]

Cawley S, Bekiranov S, Ng HH, Kapranov P, Sekinger EA, Kampa D, Piccolboni A,Sementchenko V, Cheng J, Williams AJ, Wheeler R, Wong B, Drenkow J, Yamanaka M,Patel S, Brubaker S, Tammana H, Helt G, Struhl K, Gingeras TR. (2004) "Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs." Cell. Feb 116:499-509. [PubMed]

Bernstein BE, Kamal M, Lindblad-Toh K, Bekiranov S, Bailey DK, Huebert DJ,McMahon S, Karlsson EK, Kulbokas EJ 3rd, Gingeras TR, Schreiber SL, Lander ES. (2005) "Genomic maps and comparative analysis of histone modifications in human and mouse." Cell. Jan 120:169-81. [PubMed]