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Kenneth S. Zaret, PhD is the Joseph Leidy Professor in the Department of Cell and Developmental Biology at the Perelman School of Medicine, University of Pennsylvania, and Director of the Institute for Regenerative Medicine at UPenn. He is a recipient of the Hans Popper Basic Science Award from the American Association for the Study of Liver Diseases and the American Liver Foundation, a fellow of the American Association for the Advancement of Science, and a member of the American Association of Arts and Sciences, the European Molecular Biology Organization, and the National Academy of Sciences.

Dr. Zaret investigates the basis for cell fate changes in mammalian embryos and has unveiled how signaling induces the liver in development, how certain transcription factors act as pioneers by targeting silent, compact chromatin, and how H3K9me3 heterochromatin barriers to reprogramming can be overcome by transiently down-regulating newly discovered heterochromatin proteins.

Dr. Zaret’s work provided a paradigm-shifting view in understanding how cell fate changes are initiated at the molecular level. His work uniquely focused on the intersection between embryonic development and the biochemical activities of gene regulatory proteins in chromatin, and subsequently he applied his findings to the field of cellular reprogramming.

Dr. Zaret discovered that certain gene regulatory proteins recognize their target DNA motif, or a partial motif, on nucleosomes and thereby bind silent gene sequences in chromatin. He discovered that such proteins bind genes in embryonic progenitor cells, prior to the activation of gene expression, endowing the competence to differentiate. His group found that the initial chromatin binding factors, but not later binding transcription factors, could expose an underlying nucleosome in a target site-dependent fashion on linker histone-compacted nucleosome arrays in vitro. He named the nucleosome-binding transcription factors as pioneer factors. His group recently showed that pioneer factors enable nucleosome remodelers, not vice-versa, in opening the chromatin more widely. His discovery of pioneer factors has explained the basis for zygotic genome induction, diverse types of cell fate changes, iPS and other forms of reprogramming, and hormone-responsive breast and prostate tumors.

Dr. Zaret’s laboratory discovered that certain H3K9me3-heterochromatin regions can impede pioneer factor binding and thereby impair different types of cellular reprogramming. His laboratory found that H3K9me3-heterochromatin is far more dynamic in embryonic development than had been appreciated and that genetic perturbation leads to profound disruptions of organogenesis and lethality. His group discovered scores of H3K9me3-heterochromatin proteins whose transient inactivation enables many heterochromatic genes to be activated during hepatic reprogramming. The discoveries are shifting the epigenetics and stem cell fields towards understanding how H3K9me3-heterochromatin can be modulated to enhance cellular differentiation.

Dr. Zaret has made fundamental discoveries of molecular signals in the embryo that induce liver and pancreas cell fates from early embryonic endoderm. The tissue-inducing signals have been employed by labs around the world to make novel liver cells from human embryonic stem cells. Dr. Zaret also discovered that during early liver development, endothelial cell progenitors provide signals to the nascent hepatoblasts, prior to the formation of blood vessels, which are important for liver outgrowth and morphogenetic development. The early signaling role of endothelial cells is employed by diverse labs to enhance tissue organoids from stem cells, to model disease, and enhance future therapeutics.

In summary, Dr. Zaret’s distinct intersection of developmental biology and biochemistry led to his discoveries in organogenesis and of pioneer factors, with the latter explaining how cell fate changes are initiated. The work impacts our ability to manipulate embryogenesis and stem cell differentiation, reprogramming, and diverse other areas of human physiology, making Dr. Zaret an outstanding candidate for the Ogawa-Yamanaka Stem Cell Prize.

References

1. "Zaret Laboratory". upenn.edu. Retrieved June 27, 2023.
2. "Ken Zaret". upenn.edu. Retrieved June 27, 2023.
3. "News from the National Academy of Sciences". nasonline.org. Retrieved June 27, 2023.
4. "The Joseph Leidy Professorship of Cell & Developmental Biology". med.upenn.edu/. Retrieved June 27, 2023.
5. "Zaret Laboratory". upenn.edu. Retrieved June 27, 2023.

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