Chromatin packing: the ‘operating system’ of the human genome
The behavior of organisms is determined by both their genetic code and their capacity to explore a transcriptional landscape of thousands of genes to create new functional states. Furthermore, many human diseases result from the dysregulation of the complex interactions between tens to thousands of genes. Gene transcription regulation occurs across a hierarchy of length scales: from the nucleosomal level through alterations in local DNA accessibility (~10nm) to genome compartmentalization conferred by organization of DNA into a range of domains (~100nm) and to chromatin packing, which works across all supranucleosomal length scales (>10nm) and affects global patterns of gene expression via systems-level physical factors such as chromatin nanoenvironment (e.g. ionic environment, pH, molecular crowding). Examples of global genomic reprogramming involving chromatin packing include stem cell plasticity, tissue regeneration, and diseases such as cancer, atherosclerosis, and neurodegeneration. Regulation of cells, not merely through genetic manipulation but also through engineering changes at the level of chromatin packing, may eventually allow combating disease and design organisms that can remediate environmental problems or adapt to environmental change.
The Backman Laboratory leverages the convergent science approach that bridges new technology platforms (nanoimaging and physics-based modeling of transcriptional molecular processes) with computational genomics in order to decode the role of chromatin packing in gene expression regulation. We study how chromatin packing regulates cells’ transcriptional access to their genomic space and how this regulation can be edited
Macrogenomic Engineering
The behavior of organisms is determined by both their genetic code and their capacity to explore a transcriptional landscape of thousands of genes to create new functional states. Many human diseases result from the dysregulation of the complex interactions between thousands of genes. Genetic engineering techniques such as CRISPR-Cas9 have recently emerged to edit specific genes. However, approaches for the transcriptional modulation of many genes simultaneously in a predictive manner are lacking. We develop complementary strategies for global-scale transcriptional engineering. If genes can be compared with ‘hardware’ and the epigenetic regulation as ‘software’, then chromatin packing is the ‘operating system’. We develop technologies to reversibly and predictably reprogram the chromatin’s “operating system” and to regulate global patterns of gene expression in order to combat diseases and to reversibly engineer living systems to respond to stresses in a beneficial manner.
Highlight Paper: L.M. Almassalha, G.M. Bauer, J. Chandler, S. Gladstein, I. Szleifer, H.K. Roy, V. Backman, “The greater genomic landscape: the heterogeneous evolution of cancer”, Cancer Research, 76(19), 5605-9 (2016). PMC5084919.
L.M. Almassalha, A. Tiwari, P.T. Ruhoff, Y. Stypula-Cyrus, H. Matsuda, M.A. Dela Cruz, J.E. Chandler, C. White, C. Maneval, H. Subramanian, I. Szleifer, H. Roy, V. Backman, “The global relationship between chromatin physical topology, fractal structure, and gene expression”, Scientific Reports, 7, 41061 (2017). PMC5259786.