Abstract
The mammalian genome is replicated in a defined temporal sequence during S phase of each cell cycle, via bursts of initiation that replicate megabase-sized segments within 45-60 minutes. Since chromatin is assembled at the replication fork, and different types of chromatin are assembled at different times, changes in replication timing have the potential to rapidly alter chromatin composition across these large chromosomal segments. The speaker has comprehensively mapped differentiation-induced changes in replication timing and how they relate to changes in transcription and sub-nuclear organization of chromatin during the course of the cell cycle and differentiation, using mouse and human embryonic stem cell (mESC and hESC) systems in his laboratory. Developmentally programmed changes in replication timing affect at least half the genome and occur in discrete units (“replication domains; RDs”) of 400-800 kb that accompany spatial re-organization of the affected chromosome domains. Replication domains correspond to topologically-associating domains (TADs) of chromosomes identified by chromosome conformation capture. The boundaries of RDs/TADs are stable in different cell types, while their 3D arrangement in the nucleus, chromatin structure and replication timing are cell-type specific and change coordinately during cell fate transitions and in domains that show disease-specific replication timing alterations. By contrast, within a given self-renewing cell type or disease state, replication timing is stably maintained and is robust to perturbations in many chromatin regulatory molecules, with the singular exception of the gene encoding the poorly characterized protein Rif1. Current work is aimed at identifying causal links between replication timing, transcription and 3D chromosome architecture using CRISPR-targeted deletions and inversion as well as ectopic insertion strategies.
About the speaker
Prof David Gilbert received his PhD in genetics from Stanford University in 1990. Prior to joining Florida State University in 2006, he worked with the University of New York Health Center since 1994. There he was promoted to become Professor of Biochemistry and Molecular Biology. He is currently the J. Herbert Taylor Distinguished Professor of Molecular Biology at Florida State University.
Prof Gilbert is a renowned biologist in mammalian chromosome biology. He is known for his pioneering work on defining the mechanism and landscapes that regulate the timing of DNA replication along structural and functional domains of mammalian chromosomes. He has been on the editorial boards of Epigenetics Society and Journal of Cell Biology since 2008 and Molecular Cell Biology since 2017.
Prof Gilbert was awarded with the NIH Career Enhancement (K18) Award for Stem Cell Research by the US National Institutes of Health (NIH) in 2004. In 2011, he was selected to be the member of NIH ENCODE and mouse ENCODE consortia. He was also elected / selected a member of American Society of Hematology (2013) and of the International Society of Stem Cell Research (2014)
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