Our genome represents Gigabytes of information that rest on a physical material known as chromatin. Throughout the lifetime of the cell, this information is copied, corrected, and modified by complex molecular assemblies that have evolved to interact with the chromatin via highly intricate mechanisms. In the context of all this activity, the fundamental task of the chromatin is to protect the delicate DNA polymer. The regulatory hub for these duties is a disc-shaped nucleoprotein known as the nucleosome, the smallest repeating architectural unit of chromatin.
The nucleosome is composed of approximately 150 base pairs of nucleic acid that are wrapped around four pairs of highly conserved proteins known as histones. Covalent modifications in the histones and the surrounding nucleic acid alter also the physical properties of the nucleosomes, which in turn, influence their interactions with chromatin factors. Some nucleosomes become more flexible such that their DNA is loose whereas others become more rigid such that their DNA is less accessible. Some other nucleosomes are decorated with electrostatic charges and novel functional groups that invite the assembly and action of transcription factors, chromatin remodelers, and modifier enzymes.
This diversity of nucleosomes introduces an additional layer of genetic information, i.e., the epigenetic code, and the exploitation of biophysical processes in the expression and inheritance of the epigenetic code invites a quantitative approach for their study.
The goal in our group is to elucidate the biophysical processes that influence the regulation of gene expression and inheritance at the molecular level. We employ tools of molecular modeling, atomistic simulations, and enhanced sampling to study how structural modifications in chromatin translate into differences in dynamics. These differences are often associated with distinct functions and purposes according to experimental input. This association sets a basis for our simulations to provide a molecular picture of the underlying mechanisms.
One example of an epigenetic modification is histone variant exchange as illustrated below. Centromeric nucleosomes are characterized by a unique histone variant called CENP-A (ice-blue) which replaces its canonical counterpart, histone H3 (dark blue). This alteration results in more flexible DNA termini in the centromeric nucleosome (bottom right) compared to the canonical nucleosome (bottom left). As it turns out, this flexibility is a physical feature necessary for the mitotic fidelity and proper segregation of chromosomes during cell division.
Zhou BR, Feng H, Kale S, Fox T, Khant H, de Val N, Ghirlando R, Panchenko AR, Bai Y. Distinct Structures and Dynamics of Chromatosomes with Different Human Linker Histone Isoforms.. Molecular cell. 2020 November . doi:10.1016/j.molcel.2020.10.038.
Boopathi R, Danev R, Khoshouei M, Kale S, Nahata S, Ramos L, Angelov D, Dimitrov S, Hamiche A, Petosa C, Bednar J. Phase-plate cryo-EM structure of the Widom 601 CENP-A nucleosome core particle reveals differential flexibility of the DNA ends.. Nucleic acids research. 2020 June ; 48 (10) : 5735-5748. doi:10.1093/nar/gkaa246.
Kale S, Strickland M, Peterkofsky A, Liu J, Tjandra N. Model of a Kinetically Driven Crosstalk between Paralogous Protein Encounter Complexes.. Biophysical journal. 2019 November ; 117 (9) : 1655-1665. doi:10.1016/j.bpj.2019.09.035.
Strickland M, Kale S, Strub MP, Schwieters CD, Liu J, Peterkofsky A, Tjandra N. Potential Regulatory Role of Competitive Encounter Complexes in Paralogous Phosphotransferase Systems.. Journal of molecular biology. 2019 May ; 431 (12) : 2331-2342. doi:10.1016/j.jmb.2019.04.040.
Kale S, Goncearenco A, Markov Y, Landsman D, Panchenko AR. Molecular recognition of nucleosomes by binding partners.. Current Opinion in Structural Biology. 2019 June ; 56 : 164-170. doi:10.1016/j.sbi.2019.03.010.
Hada A, Hota SK, Luo J, Lin YC, Kale S, Shaytan AK, Bhardwaj SK, Persinger J, Ranish J, Panchenko AR, Bartholomew B. Histone Octamer Structure Is Altered Early in ISW2 ATP-Dependent Nucleosome Remodeling.. Cell Reports. 2019 July ; 28 (1) : 282-294.e6. doi:10.1016/j.celrep.2019.05.106.
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