- Poste Vert Fellow, INSERM (National Institute of Health and Medical Research), 1997
- Visiting Fellow, NIDDK, NIH, 1995
- Ph.D., Weizmann Institute of Science, 1991
- B.Sc. (Hons), University of the Witwatersrand, 1985
- B.Sc., University of the Witwatersrand, 1984
The purpose of our studies is to understand in vivo chromatin structure at the 30-nm fiber level and beyond and to extend current hydrodynamic methodology for the study of challenging biomacromolecular interactions.
Genomic DNA within the cell nucleus is packaged, together with histones and other functional proteins, into chromatin. We are interested in understanding its organization within chromatin, as well as the topological constraints imposed upon it within the higher-order arrangement imposed by nonhistone proteins, such as CTCF. These studies are important as they will allow us to better understand the structure of both the ‘open’ and condensed chromatin fiber in vivo. Furthermore, as chromatin plays an essential role in processes such as DNA transcription, replication, repair, and recombination, its organization is fundamental to understanding the finer details of these processes.
Macromolecular interactions define most biological processes. We utilize thermodynamic and hydrodynamic methods to characterize biological assemblies in terms of their shape, stoichiometry, and affinity of interaction. These studies complement current biochemical, structural, and physiological investigations within the National Institute of Diabetes and Digestive and Kidney Diseases. They further provide a platform for the development and improvement of current biophysical and thermodynamic methodologies, particularly analytical ultracentrifugation.
Applying our Research
It is now clear that the higher-order chromatin structure is intimately involved with nuclear processes such as DNA translation, replication, repair, and recombination. Recent studies have demonstrated that a number of human diseases are associated with abnormalities in these processes at the chromatin level.
Furthermore, the higher-order chromatin structure is maintained and regulated by a plethora of remodeling and modifying protein complexes. Mutations in some of these proteins have been associated with cancer and developmental disorders, altogether highlighting the significance of chromatin structure in proper gene regulation and disease. It is anticipated that an improved understanding of chromatin structure and its relation to related nuclear processes at a molecular level will help further unravel its connection to related abnormalities.
Need for Further Study
Research is still needed to understand the chromatin compaction on the chromosome level and to improve methodologies for the study of multiprotein/nucleic acid assemblies.
- Distinct Structures and Dynamics of Chromatosomes with Different Human Linker Histone Isoforms.
- Zhou BR, Feng H, Kale S, Fox T, Khant H, de Val N, Ghirlando R, Panchenko AR, Bai Y.
- Mol Cell (2021 Jan 7) 81:166-182.e6. Abstract/Full Text
- Structures of ISCth4 transpososomes reveal the role of asymmetry in copy-out/paste-in DNA transposition.
- Kosek D, Hickman AB, Ghirlando R, He S, Dyda F.
- EMBO J (2021 Jan 4) 40:e105666. Abstract/Full Text
Research in Plain Language
The human genome (DNA) provides the complete code for our genetic information. Even though its recent decoding has proven to be very useful, the information provided still needs to be understood in more detail. We are interested in learning more about the three-dimensional structure of chromatin, the combination of DNA and proteins that make up the contents of the cell nucleus. In particular, we want to better understand how the structure of chromatin is related to activation or inactivation of specific regions of the genome. Gene activity or inactivity gives the cell control over structure and function, and helps cells develop and assemble to form the molecular machines that keep an organism alive. An understanding of these molecular machines requires a keen understanding of the chemical and biological processes involved deep within the cell—processes that translate gene activity into cellular action. We can learn more about these processes by studying the interactions of chromatin and its specific proteins. The results of our studies can help other scientists use this information to combat human disease.