Genome Structure & Function

Genome Structure & Function

Studies

The Gilbert Group

The focus of the Gilbert research group is to understand how human chromosomes are organized within the nucleus to carry out their functions. Their research program is built on the understanding that all cells replicate their DNA in a temporal sequence that is specific to each cell type and is disrupted in all diseases studied to date. However, both the mechanisms of this “replication timing” program and its biological significance remain a mystery.

Faithfully duplicating our DNA is arguably the most fundamental thing that our cells do, and mistakes in this process are major drivers of disease, yet we understand very little about its regulation. Replication timing is clearly related to the 3-dimensional organization of chromosomes such that structural and functional units of chromosomes replicate coordinately, often through the synchronous firing of clusters of replication origins that encompass domains of approximately 0.5Mb. Each of these replication domains is programmed to replicate at a specific time during S-phase. In general, transcriptionally active (euchromatin) domains replicate early in S-phase and transcriptionally silent (heterochromatin) domains replicate late. The order in which these segments replicate is disrupted in many diseases, including all cancers. However, there is still no conclusive understanding of why replication takes place in the order it does, or why it is different in each of the tissues of our body.

The primary motivation for Dr. Gilbert’s research is that these units that we call “replication domains provide us with a molecular handle into the higher order structural and functional organization of chromosomes. They hypothesize that, since it is not just DNA that replicates but the entire epigenome and its 3D organization, controlling where and when replication takes place can serve as a convenient means for cells to maintain stable epigenetic states or to change those states during cell fate transitions. The work in the Gilbert laboratory can be divided into the following major areas: the developmental regulation of DNA replication, regulation of replication timing during the cell cycle, discovery of what regulates the sites where replication initiates, and human replication origins.

Donate Now Help us give every patient a fighting chance.

Select Publications

Daniel A. Bartlett, Vishnu Dileep, Steve Henikoff, David M. Gilbert. High throughput genome-wide single cell protein:DNA binding site mapping by targeted insertion of promoters (TIP-seq). bioRxiv 2021.03.17.435909; doi: https://doi.org/10.1101/2021.03.17.435909.

Weitao Wang, Kyle Klein, Karel Proesmans, Hongbo Yang, Claire Marchal, Xiaopeng Zhu, Tyler Borman, Alex Hastie, Zhiping Weng, John Bechhoefer, Chun-Long Chen, David M. Gilbert, Nicholas Rhind. Genome-Wide Identification of Early-Firing Human Replication Origins by Optical Replication Mapping. MOLECULAR CELL, 81:2975-2988. (PMID: 34157308)

PDF

Kyle N. Klein, Peiyao A. Zhao, Xiaowen Lyu, Daniel A. Bartlett, Amar Singh, Ipek Tasan, Lotte P. Watts, Shin-ichiro Hiraga, Toyoaki Natsume, Xuemeng Zhou, Danny Leung, Masato T. Kanemaki, Anne D. Donaldson, Huimin Zhao, Stephen Dalton, Victor G. Corces, David M. Gilbert. Replication timing maintains the global epigenetic state in human cells SCIENCE, 2021 April 23;372(6540): 371-378. doi: 10.1126/science.aba5545. Epub 2021 Apr 22. PMID: 33888635.

Sarni, D., Sasaki, T., Miron, K., Tur-Sinai, M.I., Rivera-Mulia, J.C., Magnuson, B., Jjungman, M., Gilbert D.M. and Karem, B. (2020) 3D genome organization contributes to genome instability at fragile sites. NAT. COMM., 11(1):3613 (PMID: 32680994).

PDF

Marchal C., Sima J., Gilbert D.M. (2019) Control of DNA replication timing in the 4D genome. NATURE REV. MOL. CELL. BIOL., 20:721-737 (PMID: 31477886)

Sima J, Chakraborty A, Dileep V, Michalski M, Klein K.N., Holcomb N.P., Turner J.L., Paulsen M.T., Rivera-Mulia JC, Trevilla-Garcia C, Bartlett DA, Zhao PA, Washburn BK, Nora EP, Kraft K, Mundlos S, Bruneau BG, Ljungman M, Fraser P, Ay F, Gilbert DM. (2019) Identifying cis-Elements for Spatiotemporal Control of Mammalian DNA Replication. CELL 176:816-830 (PMID 30595451)

PDF

We need your help


Our research programs are funded primarily by grants from the National Institutes of Health (NIH). Private donations help to accelerate the progress of research through the purchase of laboratory supplies and equipment or the recruitment of additional laboratory personnel. Thank you!

Donate Now