Kenneth Zaret

Last updated
Kenneth S. Zaret
BornMarch 7, 1955
NationalityAmerican
Alma materUniversity of Rochester
Scientific career
FieldsBiology
InstitutionsUniversity of California, San Francisco (1982-1985)
Brown University (1986-1999)
University of Pennsylvania (1999-)

Kenneth S. Zaret (born March 7, 1955) is a 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, [1] and a member of the American Academy of Arts and Sciences, [2] the European Molecular Biology Organization, [3] and the National Academy of Sciences. [4]

Contents

Career

Zaret developed an interest in the natural world when he was growing up, and while in high school gained a fellowship from the National Science Foundation to do some research at a medical school in Philadelphia. This introduced him to laboratory science, and eventually to biology and biochemistry at college. [5] Zaret gained his BA in Biology and then a PhD in Biophysics at the University of Rochester. After postdoctoral research at the University of California, San Francisco, Zaret moved to Brown University in 1986, where he worked first in the Biochemistry section, and later in the Department of Molecular Biology, Cell Biology, and Biochemistry at Brown University Medical School. In 1999, Zaret moved to the Basic Science Division at the Fox Chase Cancer Center in Philadelphia. [5] [6]

Research

As a graduate student with Fred Sherman at the University of Rochester School of Medicine (1977-1982), Zaret discovered that when genes in DNA are transcribed into messenger RNA (mRNA), signals in the DNA cause a coupled termination of transcription and processing of the mRNA by polyadenylation. [7] As a postdoctoral fellow with Keith Yamamoto at the University of California, San Francisco (1982-1985), Zaret discovered that when the steroid receptor for glucocorticoid becomes activated by hormone, the receptor loosens up the local chromosome structure at target genes that then become activated. [8]

Zaret's laboratory investigates the ways that genes are activated and different cell types are specified in embryonic development, regenerating tissues, and disease. His group initially focused on the dynamics in cell signaling, gene regulatory proteins, and chromosome structure in the early mammalian embryo, in the development of the liver. [9] His laboratory discovered embryonic signals that induce the formation of the liver, [10] that there is a bipotential precursor population in the embryo for the liver and pancreas, [11] and that primitive blood vessel cells, before they form blood vessels, signal to early liver cells to develop morphologically into the liver. [12] The findings from his laboratory have been used by other laboratories to engineer new liver cells and liver tissue from stem cells. [13]

His laboratory discovered and named pioneer transcription factors that can bind to compacted chromosome domains harboring silent genes, and that enable cooperative events with other proteins to allow silent genes to turn on. [14] The mechanism of targeting of silent, compacted chromosome domains by pioneer factors has since been found by many laboratories to control the earliest stages of embryonic development and enable cell fate switching in development, regeneration, and human cancers. [15]

Zaret's laboratory revealed an unexpectedly dynamic nature of the most compacted form of chromosome structure, called heterochromatin, during embryonic development. [16] They also found that the H3K9me3 subtype of heterochromatin is the most repressive form to overcome when reprogramming cell fates. [17] These findings can be applied to controlling cell fates at will for modeling human disease and developing cell-based therapies.


Related Research Articles

<span class="mw-page-title-main">Euchromatin</span> Lightly packed form of chromatin that is enriched in genes

Euchromatin is a lightly packed form of chromatin that is enriched in genes, and is often under active transcription. Euchromatin stands in contrast to heterochromatin, which is tightly packed and less accessible for transcription. 92% of the human genome is euchromatic.

Heterochromatin is a tightly packed form of DNA or condensed DNA, which comes in multiple varieties. These varieties lie on a continuum between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a role in the expression of genes. Because it is tightly packed, it was thought to be inaccessible to polymerases and therefore not transcribed; however, according to Volpe et al. (2002), and many other papers since, much of this DNA is in fact transcribed, but it is continuously turned over via RNA-induced transcriptional silencing (RITS). Recent studies with electron microscopy and OsO4 staining reveal that the dense packing is not due to the chromatin.

FOXproteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryonic development. FOX proteins also have pioneering transcription activity by being able to bind condensed chromatin during cell differentiation processes.

RNA-induced transcriptional silencing (RITS) is a form of RNA interference by which short RNA molecules – such as small interfering RNA (siRNA) – trigger the downregulation of transcription of a particular gene or genomic region. This is usually accomplished by posttranslational modification of histone tails which target the genomic region for heterochromatin formation. The protein complex that binds to siRNAs and interacts with the methylated lysine 9 residue of histones H3 (H3K9me2) is the RITS complex.

<span class="mw-page-title-main">TCF7L2</span> Protein-coding gene in humans

Transcription factor 7-like 2 , also known as TCF7L2 or TCF4, is a protein acting as a transcription factor that, in humans, is encoded by the TCF7L2 gene. The TCF7L2 gene is located on chromosome 10q25.2–q25.3, contains 19 exons. As a member of the TCF family, TCF7L2 can form a bipartite transcription factor and influence several biological pathways, including the Wnt signalling pathway.

<span class="mw-page-title-main">Liver receptor homolog-1</span> Protein-coding gene in the species Homo sapiens

The liver receptor homolog-1 (LRH-1) also known as totipotency pioneer factor NR5A2 is a protein that in humans is encoded by the NR5A2 gene. LRH-1 is a member of the nuclear receptor family of intracellular transcription factors.

<span class="mw-page-title-main">Induced pluripotent stem cell</span> Pluripotent stem cell generated directly from a somatic cell

Induced pluripotent stem cells are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka and Kazutoshi Takahashi in Kyoto, Japan, who together showed in 2006 that the introduction of four specific genes, collectively known as Yamanaka factors, encoding transcription factors could convert somatic cells into pluripotent stem cells. Shinya Yamanaka was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent."

<span class="mw-page-title-main">RUNX1</span> Protein-coding gene in humans

Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) is a protein that in humans is encoded by the RUNX1 gene.

<span class="mw-page-title-main">PDX1</span> A protein involved in the pancreas and duodenum differentiation

PDX1, also known as insulin promoter factor 1, is a transcription factor in the ParaHox gene cluster. In vertebrates, Pdx1 is necessary for pancreatic development, including β-cell maturation, and duodenal differentiation. In humans this protein is encoded by the PDX1 gene, which was formerly known as IPF1. The gene was originally identified in the clawed frog Xenopus laevis and is present widely across the evolutionary diversity of bilaterian animals, although it has been lost in evolution in arthropods and nematodes. Despite the gene name being Pdx1, there is no Pdx2 gene in most animals; single-copy Pdx1 orthologs have been identified in all mammals. Coelacanth and cartilaginous fish are, so far, the only vertebrates shown to have two Pdx genes, Pdx1 and Pdx2.

<span class="mw-page-title-main">Histone H2A.Z</span> Protein-coding gene in the species Homo sapiens

Histone H2A.Z is a protein that in humans is encoded by the H2AZ1 gene.

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones. The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. The H2AFZ gene encodes a replication-independent member of the histone H2A family that is distinct from other members of the family. Studies in mice have shown that this particular histone is required for embryonic development and indicate that lack of functional histone H2A leads to embryonic lethality.

<span class="mw-page-title-main">REG3A</span> Protein-coding gene in the species Homo sapiens

Regenerating islet-derived protein 3 alpha formerly known as HIP/PAP and peptide 23 is a protein that in humans is encoded by the REG3A gene.

Neurogenins, often abbreviated as Ngn, are a family of bHLH transcription factors involved in specifying neuronal differentiation. The family consisting of Neurogenin-1, Neurogenin-2, and Neurogenin-3, plays a fundamental role in specifying neural precursor cells and regulating the differentiation of neurons during embryonic development. It is one of many gene families related to the atonal gene in Drosophila. Other positive regulators of neuronal differentiation also expressed during early neural development include NeuroD and ASCL1.

<span class="mw-page-title-main">Neurogenin-3</span> Mammalian protein found in Homo sapiens

Neurogenin-3 (NGN3) is a protein that in humans is encoded by the Neurog3 gene.

<span class="mw-page-title-main">Cell potency</span> Ability of a cell to differentiate into other cell types

Cell potency is a cell's ability to differentiate into other cell types. The more cell types a cell can differentiate into, the greater its potency. Potency is also described as the gene activation potential within a cell, which like a continuum, begins with totipotency to designate a cell with the most differentiation potential, pluripotency, multipotency, oligopotency, and finally unipotency.

<span class="mw-page-title-main">FOXA2</span> Mammalian protein found in Homo sapiens

Forkhead box protein A2 (FOXA2), also known as hepatocyte nuclear factor 3-beta (HNF-3B), is a transcription factor that plays an important role during development, in mature tissues and, when dysregulated or mutated, also in cancer.

Pioneer factors are transcription factors that can directly bind condensed chromatin. They can have positive and negative effects on transcription and are important in recruiting other transcription factors and histone modification enzymes as well as controlling DNA methylation. They were first discovered in 2002 as factors capable of binding to target sites on nucleosomal DNA in compacted chromatin and endowing competency for gene activity during hepatogenesis. Pioneer factors are involved in initiating cell differentiation and activation of cell-specific genes. This property is observed in histone fold-domain containing transcription factors and other transcription factors that use zinc finger(s) for DNA binding.

Epigenetics of human development is the study of how epigenetics effects human development.

<span class="mw-page-title-main">Pancreatic progenitor cell</span>

Pancreatic progenitor cells are multipotent stem cells originating from the developing fore-gut endoderm which have the ability to differentiate into the lineage specific progenitors responsible for the developing pancreas.

<span class="mw-page-title-main">Thomas Jenuwein</span> German scientist

Thomas Jenuwein is a German scientist working in the fields of epigenetics, chromatin biology, gene regulation and genome function.

H3K9me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 9th lysine residue of the histone H3 protein and is often associated with heterochromatin.

References

  1. ↑ "Elected Fellows". aaas.org. Retrieved June 30, 2023.
  2. ↑ "Members Elected in 2021, by Class & Section". amacad.org. 6 December 2021. Retrieved June 30, 2023.
  3. ↑ "EMBO elects 67 new members and associate members". embo.org. 6 July 2022. Retrieved June 30, 2023.
  4. ↑ "Four from Penn elected to the National Academy of Sciences". upenn.edu. 3 May 2023. Retrieved June 30, 2023.
  5. 1 2 Senior, Kathryn (2010). "An interview with Ken Zaret". Development. 137: 3151–3152.
  6. ↑ "Kenneth S. Zaret". www.nasonline.org.
  7. ↑ "DNA sequence required for efficient transcription termination in yeast" (PDF). Cell. March 1982. Retrieved June 30, 2023.
  8. ↑ "Reversible and persistent changes in chromatin structure accompany activation of a glucocorticoid-dependent enhancer element" (PDF). Cell. August 1984. Retrieved June 30, 2023.
  9. ↑ Zaret, Kenneth S.; Grompe, Markus (December 5, 2008). "Generation and Regeneration of Cells of the Liver and Pancreas". Science. 322 (5907): 1490–1494. Bibcode:2008Sci...322.1490Z. doi:10.1126/science.1161431. PMC   2641009 . PMID   19056973.
  10. ↑ Jung, Joonil; Zheng, Minghua; Goldfarb, Mitchell; Zaret, Kenneth S. (June 18, 1999). "Initiation of Mammalian Liver Development from Endoderm by Fibroblast Growth Factors". Science. 284 (5422): 1998–2003. doi:10.1126/science.284.5422.1998. PMID   10373120 . Retrieved June 30, 2023.
  11. ↑ "A bipotential precursor population for pancreas and liver within the embryonic endoderm". Development. March 15, 2001. Retrieved June 30, 2023.
  12. ↑ Matsumoto, Kunio; Yoshitomi, Hideyuki; Rossant, Janet; Zaret, Kenneth S. (September 27, 2001). "Liver Organogenesis Promoted by Endothelial Cells Prior to Vascular Function". Science. 294 (5542): 559–563. Bibcode:2001Sci...294..559M. doi:10.1126/science.1063889. PMID   11577199. S2CID   44496195 . Retrieved June 30, 2023.
  13. ↑ Thompson, Wendy L.; Takebe, Takanori (January 10, 2021). "Human liver model systems in a dish". Development, Growth & Differentiation. 63 (1): 47–58. doi:10.1111/dgd.12708. PMC   7940568 . PMID   33423319.
  14. ↑ Cirillo, Lisa Ann; Lin, Frank Robert; Cuesta, Isabel; Friedman, Dara; Jarnik, Michal; Zaret, Kenneth S. (February 2002). "Opening of Compacted Chromatin by Early Developmental Transcription Factors HNF3 (FoxA) and GATA-4". Molecular Cell. 9 (2): 279–289. doi: 10.1016/S1097-2765(02)00459-8 . PMID   11864602 . Retrieved June 30, 2023.
  15. ↑ Zaret, Kenneth S. (September 4, 2020). "Pioneer Transcription Factors Initiating Gene Network Changes". Annual Review of Genetics. 54: 367–385. doi:10.1146/annurev-genet-030220-015007. PMC   7900943 . PMID   32886547.
  16. ↑ Nicetto, Dario; Donahue, Greg; Jain, Tanya; Peng, Tao; Sidoli, Simone; Sheng, Lihong; Montavon, Thomas; Becker, Justin S.; Grindheim, Jessica M.; Blahnik, Kimberly; Garcia, Benjamin A.; Tan, Kai; Bonasio, Roberto; Jenuwein, Thomas; Zaret, Kenneth S. (January 3, 2019). "H3K9me3-heterochromatin loss at protein-coding genes enables developmental lineage specification". Science. 363 (6424): 294–297. Bibcode:2019Sci...363..294N. doi:10.1126/science.aau0583. PMC   6664818 . PMID   30606806.
  17. ↑ McCarthy, Ryan L.; Kaeding, Kelsey E.; Keller, Samuel H.; Zhong, Yu; Xu, Liqin; Hsieh, Antony; Hou, Yong; Donahue, Greg; Becker, Justin S.; Alberto, Oscar; Lim, Bomyi; Zaret, Kenneth S. (August 5, 2021). "Diverse heterochromatin-associated proteins repress distinct classes of genes and repetitive elements". Nature Cell Biology. 23 (8): 905–914. doi:10.1038/s41556-021-00725-7. PMC   9248069 . PMID   34354237.
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