Investigators

Dave Gilbert, Ph.D.

Professor
Genome Structure & Function
The Gilbert Laboratory

Research Focus

Chromosomes are central to cellular identity, development and heredity, yet we still have a primitive understanding of how they influence cellular and organismal phenotypes. With the exception of highly localized functions such as transcription of specific genes, involving a tiny fraction of the genomic space, the field of Chromosome Biology has remained largely a descriptive science. Modern innovative genomics and imaging applications are beginning to describe the structure of chromosomes, but cannot probe mechanism or biological significance. The broader challenge of integrating genotype with phenotype will require an understanding of previously impenetrable chromosomal mechanisms; non-genic phenomena such as higher order genome organization, replication-timing, transvection, random mono-allelic expression, chromosomally-associated lncRNAs, transposable element activity and the dark matter of chromosomes, are all enigmatic sources of phenotypic diversity. Resolving these mysteries has been difficult with traditional scientific approaches. Members of the Gilbert lab are motivated by the belief that studying the replication of DNA will reveal mechanisms that link many or perhaps all of these myriad chromosomal phenomena. This is because it is not just DNA that replicates but the entire structure of the chromosome that must be dismantled and re-built with each round of DNA replication. We also believe that there could not be a more exciting time to be doing chromosome biology; it is still full of fundamental mysteries but recent technologies have made investigation of these mysteries tractable. To achieve these goals, our research environment encourages independent pursuit of creative new ideas that challenge paradigms and push the boundaries of modern molecular and cellular biology. We promote cross-disciplinary collaboration, networking and provide mentorship focused on personalized career development.

We currently have two major research directions:

Phenotypic significance and mechanisms regulating replication timing: DNA replication of mammalian genomes is regulated in units that we call “replication domains”; RDs. We have shown that these units are also structural building blocks of chromosomes. RDs are replicated at characteristic cell-type specific times during S phase. This temporal order of replication is called Replication Timing (RT). RT is central to chromosome structure and function because the time at which RDs replicate dictates their chromatin structure and thus their epigenetic state, which in turn influences all the downstream functions of chromosomes. Consequently, defects in RT are associated with many diseases. Understanding how to manipulate these large-scale features of chromosomes to further probe their causal relationships and correct defects for therapeutic purposes will require a detailed understanding of the mechanisms regulating RT. In particular, we have discovered DNA sequence-based regulatory elements that regulate replication timing. We are now elucidating the mechanisms by which they function, refining the DNA sequence code that defines the tissues in which they function. We are also mining the variation in DNA sequences between individuals to link normal sequence variation to function and disease. In the future, this understanding will permit us to manipulate epigenetic states in therapeutic settings, such as emerging cellular therapies, to correct diseases or to create more robust, resilient and active cellular tools.

Replication timing as a tool to diagnose stress signatures of pathways of cancer: We have recently initiated a new approach to cancer research that addresses a longstanding need to understand why some cancers respond to treatment and others do not. We are hopeful this new approach will allow us to diagnose which molecular pathways are disrupted in cancers that defy treatment. In brief, cancer is a disease of DNA. The DNA of cancers contain unique “signatures” of re-arrangements that have occurred in the sequence of DNA due to perturbations in DNA replication that are the “modus operandi” of specific pathways gone awry. We propose that these signatures contain a code that can tell us which pathways have been disrupted, if we can crack the code. Together with a team of leaders in diverse aspects of cancer research, we have shown that we can create different patterns of DNA re-arrangements by perturbing different cancer-relevant pathways using easily manipulable cells in culture. By cataloging the DNA re-arrangements that results from perturbing various pathways, and comparing them to thousands of actual human cancers whose DNA has been sequenced, we intend to match pathways to signatures to crack this code. This will allow already existing treatments for diseases of these pathways in other contexts to be re-purposed to treat cancer.

More on Dr. Gilbert’s research and lab can be found here.


Education

Ph.D. in DNA Replication, Stanford University, 1989
B.A. in Biochemistry/Cell Biology with a minor in Philosophy, University of California, San Diego, 1982


Professional Experience

2021 – Present, Professor, San Diego BioMed
2015 – 2018 Co-Founder of the Center for Genomics and Personalized Medicine
2006 – 2020 J.H. Taylor Distinguished Professor of Molecular Biology, Florida State University
2003 – 2006 Full Professor, SUNY Upstate Medical University
1998 – 2003 Associate Professor, SUNY Upstate Medical University
1994 – 1998 Assistant Professor, SUNY Health Science Center at Syracuse


Honors and Awards

Florida State University Graduate Faculty Mentorship Award, 2016
Florida State University Distinguished Research Professor Award, 2015
FSU Biology Pfeiffer Endowed Professorship for Cancer Research, 2015 – 2018
NIH Career Enhancement Award for Stem Cell Research, 2004 – 2005
SUNY Upstate President’s Award for Excellence in Research for a Young Professor, 2002


Professional Activities

Co-Chair and Chair, Gordon Research Conference on Genome Architecture, 2017 and 2019
Chair of the NIH 4D Nucleome Consortium Cell Lines and Samples WG Phase 1 and 2, 2016 – Present
Member of NIH 4-Dimensional Nucleome (4DN) Consortium, 2011 – Present
Member, International Society for Stem Cell Research, 2014 – Present
Elected member, American Society for Hematology, 2013 – Present
Member of NIH ENCODE2, ENDOCE3, and mouseENCODE constoria, 2011 – 2018
Elected Council Delegate of the AAAS, section on Biological Sciences, 2010 – 2013
Elected Fellow of the AAAS, 2008 – Present
Editorial Board, Journal of Cell Biology, 2008 – 2021
Board Member, Epigenetics Society, 2008 – Present
Board Member, SouthEast Stem Cell Consortium (SESCC), 2008 – 2018
Peer Review, American Cancer Society, 1996 – 2004
Peer Review, NIH, 1997 – Present
Peer Review, US Army Reserve Medical Corps Breast Cancer Program, 1995 – 1998
Roache Post-Doctoral Fellowship, 1991 – 1994
Eur. Mol. Biol. Org Post-Doctoral Fellowship, 1989 – 1991

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.

Daniel Emerson, Peiyao A. Zhao, Kyle Klein, Chunmin Ge, Linda Zhou, Takayo Sasaki, Liyan Yang, Sergey V. Venvev, Johan H. Gibcus, Job Dekker, David M. Gilbert, Jennifer E. Phillips-Cremins. (2022) Cohesin-mediated loop anchors confine the location of human replication origins. NATURE, in press

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)

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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).

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Zhao, PA, Sasaki, T., Gilbert, D.M. (2020) High Resolution Repli-Seq defines the temporal choreography of initiation, elongation and termination of replication in mammalian cells. GENOME BIOL. 21: 76 (PMID: 32209126)

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Rivera-Mulia, JC, Sasaki, T., Trevilla-Garcia, C., Nakemichi, N., Knapp, DJHF, Hammond, C., Chang, B., Tyner, J.W., Devidas, M., Zimmerman, J., Klein, K.K., Somasundaram, V., Druker, B., Gruber, T., Koren, A., Eaves, C.J., Gilbert, D.M. (2019) Replication timing alterations in leukemia affect clinically relevant chromosome domains. BLOOD ADV. 3: 3201-3213 (PMID: 31698451)

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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)

Dileep, V., Wilson, KA, Marchal, C, Lyu, X, Zhao, PA, Li, B., Poulet, A., Bartlett, D.A., Rivera-Mulia, JC, Qin, Z., Robins, A.J., Schulz, T.C., Kulik, M.J., Dalton S., Corces, V.G., Gilbert, D.M. (2019) Early differentiation of human embryonic stem cells is accompanied by rapid transcriptional re-programming and discordance between replication timing and chromatin compartment. STEM CELL REPORTS 13:193-206 (PMID: 31231024)

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)

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Complete list of Dr. Gilbert’s published work.

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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!

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