Sumitabha Brahmachari

Mechanochemical control of chromosome structure, dynamics, and function

Principles governing the chromosome-scale architecture of the genome

The long genome (about one meter!) undergoes severe compaction (about a hundred thousand fold!) to fit inside the nucleus (about ten microns). One may be tempted to attribute this as a classic case of a collapsed polymer globule. However, many observations, e.g., the genome contains chromosomes (typically, tens in number) that occupy separate territories, and chromosomes harbor open and closed compartments, suggest that the reality is more complex. The current notion is that the genome is organized in a hierarchical fashion. I have used coarse-grained polymer modeling to elucidate how the collective action of various proteins constantly interacting with the genome may bring about drastic, yet predictable changes in the genomic structure, many of which characterize the species-wide chromosome organization. I use approaches integrating computational techniques (statistical mechanics, molecular dynamics, and machine learning) and experimental information to investigate structural nuances of the genome structure and its relation to function.

Compaction-Mediated Segregation of Partly Replicated Bacterial Chromosomes. S. Brahmachari, A.B. Oliveira Jr., M.F. Mello, V.G. Contessoto, and J.N. Onuchic. BioRxiv (2024). [PDF]

Temporally Correlated Active Forces Drive Segregation and Enhanced Dynamics in Chromosome Polymers. S. Brahmachari, T. Markovich, F.C. MacKintosh, and J.N. Onuchic. PRXLife 2 033003 (2024). [PDF]

Structural Reorganization and Relaxation Dynamics of Axially Stressed Chromosomes. B.S. Ruben, S. Brahmachari, V.G. Contessoto, R.R. Cheng, A.B. Oliveira Jr, M. Di Pierro, and J.N. Onuchic. Biophys. J. 122, 1633 (2023). [PDF]

PyMEGABASE: Predicting Cell-Type-Specific Structural Annotations of Chromosomes Using the Epigenome. E. Dodero-Rojas, M.F. Mello, S. Brahmachari, A.B. Oliveira Jr., V.G. Contessoto, and J.N. Onuchic. J. Mol. Biol. 435, 168180 (2023). [PDF]

Shaping the Genome via Lengthwise Compaction, Phase Separation, and Lamnina Adhesion. S. Brahmachari, V. Contessoto, M. Di Pierro, and J.N. Onuchic. Nucl. Acids Res. 50, 4258 (2022). [PDF]

3D Genomics Across the Tree of Life Identifies Condensin II as a Determinant of Architecture Type. C. Hoencamp, A.M.O Elbatsh, O. Dudchenko, S. Brahmachari, et al. Science 372, 6545 (2021). [PDF]

Chromosome Disentanglement Driven Via Optimal Compaction of Loop Extruded-Brush Structures. S. Brahmachari and J.F. Marko, Proc. Natl. Acad. Sci. USA 116, 24956 (2019). [PDF]

Statistical mechanics at the genic scales

DNA mechanics is central to protein-DNA interactions. Proteins binding to the DNA groove bend and twist DNA leading to buildup of torsion or tension along the DNA backbone. The mechanical response of DNA to the torsion or force could bring about large scale reorganization, like the formation of plectonemes. Characterizing the mechanical response of DNA to torque and force is important to understand how proteins manipulate DNA struture in the cell. Moreover, the trancribing motion of RNA polymerases twist DNA, the twist in turn may act as a mechanical regulator of gene trannscription.

Nucleosomes Play a Dual Role in Regulating Transcription Dynamics. S. Brahmachari, S. Tripathi, J.N. Onuchic, and H. Levine. PNAS 121, 28 (2024). [PDF]

DNA Supercoiling-Mediated Collective Behavior of Co-Transcribing RNA Polymerases. S. Tripathi, S. Brahmachari, J.N. Onuchic, and H. Levine. Nucl. Acids Res. 50, 1269 (2022). [PDF]

Coarse-Grained Modeling of DNA Plectoneme Formation in the Presence of Base-Pair Mismatches. P.R. Desai, S. Brahmachari, J.F. Marko, S. Das, and K.C. Neuman. Nucl. Acids Res. 48 19:10713-10725 (2020). [PDF]

DNA Mechanics and Topology. S. Brahmachari, and J.F. Marko. Biomechanics in Oncology, (Edited by C. Dong, N. Zahir, and K. Konstantopoulos; Springer International Publishing, 2018) pp. 11-39. [PDF]

Defect-Facilitated Buckling in Supercoiled Double-Helix DNAs. S. Brahmachari, A. Dittmore, Y. Takagi, K.C. Neuman, and J.F. Marko. Phys. Rev. E 97, 022416 (2018). [PDF]

Nucleation of Multiple Buckled Structures in Intertwined DNA Double Helices. S. Brahmachari, K.H. Gunn, R.D. Giuntoli, A. Mondragon, and J.F. Marko. Phys. Rev. Lett. 119, 188103 (2017). [PDF]

Supercoiling Locates Mismatches. A. Dittmore, S. Brahmachari, Y. Takagi, J.F. Marko, and K.C. Neuman. Phys. Rev. Lett. 119, 147801 (2017). [PDF]

Torque and Buckling in Stretched Intertwined Double-Helix DNAs. S. Brahmachari and J.F. Marko. Phys. Rev. E 95, 052401 (2017). [PDF]