Ming-Ming Zhou

Last updated
Ming-Ming Zhou
Ming Ming Zhou.jpg
NationalityAmerican
Alma mater East China University of Science and Technology
Michigan Technological University
Purdue University
Known forBromodomain biology and drug discovery
Scientific career
Fields Structural and Chemical Biology
Epigenetics
Drug Discovery
Institutions Icahn School of Medicine at Mount Sinai
Mount Sinai Medical Center

Ming-Ming Zhou is an American scientist who focuses on structural and chemical biology, NMR spectroscopy, and drug design. He is the Dr. Harold and Golden Lamport Professor and Chairman of the Department of Pharmacological Sciences. [1] He is also the co-director of the Drug Discovery Institute at the Icahn School of Medicine at Mount Sinai and Mount Sinai Health System in New York City, as well as Professor of Sciences. [2] Zhou is an elected fellow of the American Association for the Advancement of Science. [3]

Contents

Zhou has published more than 180 research articles and is an inventor of 28 patents. His research has been funded by grants from federal, state and private research foundations including: the National Institutes of Health, the National Science Foundation, the New York State Stem Cell Science, the Institute for the Study of Aging, the American Foundation for AIDS Research, the American Cancer Society, GlaxoSmithKline, the Michael J. Fox Foundation, the Samuel Waxman Cancer Research Foundation, [4] and the Wellcome Trust. He serves on the board of directors at the New York Structural Biology Center, as well as on the editorial boards of ACS Medicinal Chemistry Letters, the Journal of Molecular Cell Biology, [5] and Cancer Research. [6]

Biography

Zhou earned his B.E. in chemical engineering from the East China University of Science and Technology (Shanghai, PRC) in 1984. He earned his M.S. in chemistry from the Michigan Technological University in 1988 and a Ph.D. in chemistry from Purdue University in Indiana in 1993. He completed his postdoctoral fellowship at Abbott Laboratories in Chicago, Illinois, then joined the faculty of the Mount Sinai Medical School in 1997.[ citation needed ]

Research

Zhou's research is directed at better understanding the biology of epigenetic control of gene transcription of the human genome to attain both the underlying basic principles and rational design of novel chemical compounds that modulate gene expression in chromatin. His research studies have broad implications in human biology and disease, ranging from cell development, to stem cell self-renewal, differentiation, and re-programming to human cancer and inflammation, as well as neurodegenerative disorders. Among his major contributions to science are the Zhou Lab's discovery of the bromodomain as the acetyl-lysine binding domain ('chromatin reader') in gene transcription (Nature 1999) [7] and the first demonstrations of druggability and therapeutic potential of bromodomain proteins in gene transcription to treat a wide array of human diseases, including cancer and inflammation. [8] This concept has had transformative impacts in epigenetic drug discoveries in the pharmaceutical industry. [9] [10]

The Zhou Lab further discovered the tandem PHD finger of DPF3b as a first alternative to the bromodomain for acetyl-lysine binding (Nature 2010), [11] and the PAZ domain as the RNA binding domain in RNAi (Nature 2003). [12] His work also addresses the role of histone lysine methylation (Nature Cell Biol. 2008) [13] and long non-coding RNA in the epigenetic control of gene transcription in human stem cell maintenance and differentiation (Mol. Cell 2010). [14]

Zhou's work in rational design of chemical probes for mechanism-driven research led to the discovery of the HIV Tat/human co-activator PCAF interaction as a potential novel anti-HIV therapy target. [15] His group has developed chemical probes that modulate the transcriptional activity of human tumor suppressor p53 under stress conditions. His recent work includes the development of a novel gene transcriptional silencing technology. [16] Additional research discoveries include structural mechanisms as well as drug target discovery and validation for human cancers, particularly triple-negative breast cancer (TNBC), [17] [18] and inflammatory disorders such as inflammatory bowel disease (IBD) [19] [20] and multiple sclerosis. [21]

Society membership

Current and past society memberships include The Harvey Society, the Biophysical Society, [22] the American Chemical Society, the American Society for Biochemistry and Molecular Biology, the American Association for the Advancement of Science and the New York Academy of Sciences. He serves on multiple editorial boards and reviews grants for the American Cancer Society, the American Heart Association, the National Institutes of Health and the National Science Foundation.[ citation needed ]

Awards and honors

Patents

“Methods of Identifying Modulators of the FGF Receptors”US 7,108,984 B2
“ZA Loops of Bromodomains”US 7,589,167 B2
"Method of Suppressing Gene Transcription Through Histone Lysine Methylation"US 9,249,190 B2; US 10,280,408 B2
"Cyclic Vinylogous Amides as Bromodomain Inhibitors"US 9,884,806 B2; US 10,351,511 B2
"Methods of Modulating Bromodomains"US 2004/0009613 A1

Related Research Articles

<span class="mw-page-title-main">Epigenetics</span> Study of DNA modifications that do not change its sequence

In biology, epigenetics are stable heritable traits that cannot be explained by changes in DNA sequence, and the study of a type of stable change in cell function that does not involve a change to the DNA sequence. The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic mechanism of inheritance. Epigenetics usually involves a change that is not erased by cell division, and affects the regulation of gene expression. Such effects on cellular and physiological phenotypic traits may result from environmental factors, or be part of normal development. They can lead to cancer.

<span class="mw-page-title-main">Histone acetyltransferase</span> Enzymes that catalyze acyl group transfer from acetyl-CoA to histones

Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.

<span class="mw-page-title-main">Bromodomain</span>

A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the N-terminal tails of histones. Bromodomains, as the "readers" of lysine acetylation, are responsible in transducing the signal carried by acetylated lysine residues and translating it into various normal or abnormal phenotypes. Their affinity is higher for regions where multiple acetylation sites exist in proximity. This recognition is often a prerequisite for protein-histone association and chromatin remodeling. The domain itself adopts an all-α protein fold, a bundle of four alpha helices each separated by loop regions of variable lengths that form a hydrophobic pocket that recognizes the acetyl lysine.

The Structural Genomics Consortium (SGC) is a public-private-partnership focusing on elucidating the functions and disease relevance of all proteins encoded by the human genome, with an emphasis on those that are relatively understudied. The SGC places all its research output into the public domain without restriction and does not file for patents and continues to promote open science. Two recent publications revisit the case for open science. Founded in 2003, and modelled after the Single Nucleotide Polymorphism Database (dbSNP) Consortium, the SGC is a charitable company whose Members comprise organizations that contribute over $5,4M Euros to the SGC over a five-year period. The Board has one representative from each Member and an independent Chair, who serves one 5-year term. The current Chair is Anke Müller-Fahrnow (Germany), and previous Chairs have been Michael Morgan (U.K.), Wayne Hendrickson (U.S.A.), Markus Gruetter (Switzerland) and Tetsuyuki Maruyama (Japan). The founding and current CEO is Aled Edwards (Canada). The founding Members of the SGC Company were the Canadian Institutes of Health Research, Genome Canada, the Ontario Research Fund, GlaxoSmithKline and Wellcome Trust. The current Members comprise Bayer Pharma AG, Bristol Myers Squibb, Boehringer Ingelheim, the Eshelman Institute for Innovation, Genentech, Genome Canada, Janssen, Merck KGaA, Pfizer, and Takeda.

Myc is a family of regulator genes and proto-oncogenes that code for transcription factors. The Myc family consists of three related human genes: c-myc (MYC), l-myc (MYCL), and n-myc (MYCN). c-myc was the first gene to be discovered in this family, due to homology with the viral gene v-myc.

RNA activation (RNAa) is a small RNA-guided and Argonaute (Ago)-dependent gene regulation phenomenon in which promoter-targeted short double-stranded RNAs (dsRNAs) induce target gene expression at the transcriptional/epigenetic level. RNAa was first reported in a 2006 PNAS paper by Li et al. who also coined the term "RNAa" as a contrast to RNA interference (RNAi) to describe such gene activation phenomenon. dsRNAs that trigger RNAa have been termed small activating RNA (saRNA). Since the initial discovery of RNAa in human cells, many other groups have made similar observations in different mammalian species including human, non-human primates, rat and mice, plant and C. elegans, suggesting that RNAa is an evolutionarily conserved mechanism of gene regulation.

<span class="mw-page-title-main">Histone acetylation and deacetylation</span>

Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation.

Histone deacetylase inhibitors are chemical compounds that inhibit histone deacetylases.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">EZH2</span> Protein-coding gene in the species Homo sapiens

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.

<span class="mw-page-title-main">Cyclin-dependent kinase 8</span> Protein-coding gene in the species Homo sapiens

Cell division protein kinase 8 is an enzyme that in humans is encoded by the CDK8 gene.

<span class="mw-page-title-main">BRD4</span> Protein-coding gene in the species Homo sapiens

Bromodomain-containing protein 4 is a protein that in humans is encoded by the BRD4 gene.

<span class="mw-page-title-main">BRD7</span> Protein-coding gene in the species Homo sapiens

Bromodomain-containing protein 7 is a protein that in humans is encoded by the BRD7 gene.

<span class="mw-page-title-main">Bromodomain-containing protein 3</span> Protein-coding gene in the species Homo sapiens

Bromodomain-containing protein 3 (BRD3) also known as RING3-like protein (RING3L) is a protein that in humans is encoded by the BRD3 gene. This gene was identified based on its homology to the gene encoding the RING3 (BRD2) protein, a serine/threonine kinase. The gene maps to 9q34, a region which contains several major histocompatibility complex (MHC) genes.

<span class="mw-page-title-main">HOXA11-AS1</span> Long non-coding RNA from the antisense strand in the homeobox A (HOXA gene).

HOXA11-AS lncRNA is a long non-coding RNA from the antisense strand in the homeobox A. The HOX gene contains four clusters. The sense strand of the HOXA gene codes for proteins. Alternative names for HOXA11-AS lncRNA are: HOXA-AS5, HOXA11S, HOXA11-AS1, HOXA11AS, or NCRNA00076. This gene is 3,885 nucleotides long and resides at chromosome 7 (7p15.2) and is transcribed from an independent gene promoter. Being a lncRNA, it is longer than 200 nucleotides in length, in contrast to regular non-coding RNAs.

<span class="mw-page-title-main">JQ1</span> Chemical compound

JQ1 is a thienotriazolodiazepine and a potent inhibitor of the BET family of bromodomain proteins which include BRD2, BRD3, BRD4, and the testis-specific protein BRDT in mammals. BET inhibitors structurally similar to JQ1 are being tested in clinical trials for a variety of cancers including NUT midline carcinoma. It was developed by the James Bradner laboratory at Brigham and Women's Hospital and named after chemist Jun Qi. The chemical structure was inspired by patent of similar BET inhibitors by Mitsubishi Tanabe Pharma [WO/2009/084693]. Structurally it is related to benzodiazepines. While widely used in laboratory applications, JQ1 is not itself being used in human clinical trials because it has a short half life.

BET inhibitors are a class of drugs that reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated histones and transcription factors.

Polypharmacology is the design or use of pharmaceutical agents that act on multiple targets or disease pathways.

<span class="mw-page-title-main">Brpf1</span> Protein-coding gene in the species Mus musculus

Peregrin also known as bromodomain and PHD finger-containing protein 1 is a protein that in humans is encoded by the BRPF1 gene located on 3p26-p25. Peregrin is a multivalent chromatin regulator that recognizes different epigenetic marks and activates three histone acetyltransferases. BRPF1 contains two PHD fingers, one bromodomain and one chromo/Tudor-related Pro-Trp-Trp-Pro (PWWP) domain.

Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.

References

  1. ↑ "Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai".
  2. ↑ "Mount Sinai School of Medicine - Ming-Ming Zhou" . Retrieved March 8, 2011.
  3. ↑ AAAS.org staff report (30 November 2012). "AAAS Members Elected as Fellows". AAAS.org. Archived from the original on 8 August 2023. Retrieved 16 November 2023.
  4. ↑ "The Samuel Waxman Cancer Research Foundation".
  5. ↑ "Journal of Molecular Cell Biology - Editorial Board". Archived from the original on July 27, 2011. Retrieved March 8, 2011.
  6. ↑ "Cancer Research: Editorial Board" . Retrieved March 8, 2011.
  7. ↑ Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM (June 1999). "Structure and ligand of a histone acetyltransferase bromodomain". Nature. 399 (6735): 491–6. Bibcode:1999Natur.399..491D. doi:10.1038/20974. PMID   10365964. S2CID   1210925.
  8. ↑ Zeng L, Li J, Muller M, Yan S, Mujtaba S, Pan C, Wang, Z, Zhou, MM (2005). "Selective Small Molecules Blocking HIV-1 Tat and Coactivator PCAF Association". Journal of the American Chemical Society. 127 (8): 2376–7. doi:10.1021/ja044885g. PMID   15724976.
  9. ↑ Verdin E, Melanie O (April 2015). "50 Years of Protein Acetylation: From Gene Regulation to Epigenetics, metabolism and Beyond". Nature Reviews Molecular Cell Biology. 16 (4): 258–64. doi:10.1038/nrm3931. PMID   25549891. S2CID   10192177.
  10. ↑ Zaware, N, Zhou, MM (2019). "Bromodomain Biology and Drug Discovery". Nature Structural & Molecular Biology. 26 (10): 870–9. doi:10.1038/s41594-019-0309-8. PMC   6984398 . PMID   31582847.
  11. ↑ Zeng L, Zhang Q, Li S, Plotnikov AN, Walsh MJ, Zhou MM (July 2010). "Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b". Nature. 466 (7303): 258–62. Bibcode:2010Natur.466..258Z. doi:10.1038/nature09139. PMC   2901902 . PMID   20613843.
  12. ↑ Yan KS, Yan S, Farooq A, Han A, Zeng L, Zhou MM (November 2003). "Structure and conserved RNA binding of the PAZ domain". Nature. 426 (6965): 468–74. Bibcode:2003Natur.426..468Y. doi:10.1038/nature02129. PMID   14615802. S2CID   52874237.
  13. ↑ Mujtaba S, Manzur KL, Gurnon JR, Kang M, Van Etten JL, Zhou MM (August 2008). "Epigenetic transcriptional repression of cellular genes by a viral SET protein". Nature Cell Biology. 10 (9): 1114–1122. doi:10.1038/ncb1772. PMC   2898185 . PMID   19160493.
  14. ↑ Yap KL, Li S, Muñoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, Gil J, Walsh MJ, Zhou MM (June 2010). "Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a". Molecular Cell. 38 (5): 662–74. doi:10.1016/j.molcel.2010.03.021. PMC   2886305 . PMID   20541999.
  15. ↑ Zeng L, Li J, Muller M, Yan S, Mujtaba S, Pan C, Wang Z, Zhou MM (March 2005). "Selective small molecules blocking HIV-1 Tat and coactivator PCAF association". Journal of the American Chemical Society. 127 (8): 2376–7. doi:10.1021/ja044885g. PMID   15724976.
  16. ↑ "Mount Sinai researchers discover technology that silences genes" . Retrieved March 8, 2011.
  17. ↑ Shi J, Wang Y, Zeng L, Wu Y, Deng J, Zhang Q, Dong C, Li J, Rusinova E, Zhang G, Wang C, Zhu H, Evers BM, Zhou MM, Zhou BP (Feb 2014). "Disrupting the Interaction of BRD4 with Diacetylated Twist Suppresses Tumorigenesis in Basal-like Breast Cancer". Cancer Cell. 25 (2): 210–25. doi:10.1016/j.ccr.2014.01.028. PMC   4004960 . PMID   24525235.
  18. ↑ Stratikopoulos EE, Dendy M, Szabolcs M, Khaykin AJ, Lefebvre C, Zhou MM, Parsons R (2015). "Kinase and BET Inhibitors Together Clamp Inhibition of PI3K Signaling and Overcome Resistance to Therapy". Cancer Cell. 27 (6): 837–851. doi:10.1016/j.ccell.2015.05.006. PMC   4918409 . PMID   26058079.
  19. ↑ Cheung KL, Zhang F, Jaganathan A, Sharma R, Zhang Q, Konuma T, Shen T, Lee JY, Ren CY, Chen CH, Lu G, Olson MR, Zhang W, Kaplan MH, Littman DR, Walsh MJ, Xiong H, Zeng L, Zhou MM (March 2017). "Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation". Molecular Cell. 65 (6): 1068–80. doi:10.1016/j.molcel.2016.12.022. PMC   5357147 . PMID   28262505.
  20. ↑ Cheung KL, Lu GM, Sharma R, Vincek AS, Zhang RH, Plotnikov AN, Zhang F, Zhang Q, Ju Y, Hu Y, Zhao L, Han X, Meslamani J, Xu F, Jaganathan A, Shen T, Zhu H, Rusinova E, Zeng L, Zhou JC, Yang JC, Peng L, Ohlmeyer M, Walsh MJ, Zhang DY, Xiong HB, Zhou MM (March 2017). "Selective BET Bromodomain Inhibition Blocks Th17 Cell Differentiation and Ameliorates Colitis in Mice". Proceedings of the National Academy of Sciences of the United States of America. 114 (11): 2952–7. doi: 10.1073/pnas.1615601114 . PMC   5358349 . PMID   28265070.
  21. ↑ Gacias-Monserrat M, Gerona-Navarro G, Plotnikov AN, Zhang GT, Zeng L, Kaur J, Moy G, Rusinova E, Rodríguez-Fernández Y, Matikainen B, Joshua J, Vincek A, Joshua J, Casaccia P, Zhou MM (July 2014). "Selective Chemical Modification of Gene Transcription Favors Oligodendrocyte Lineage Progression". Chemistry & Biology. 21 (7): 841–54. doi:10.1016/j.chembiol.2014.05.009. PMC   4104156 . PMID   24954007.
  22. ↑ "Biophysical Society" . Retrieved March 8, 2011.
  23. ↑ "GlaxoSmithKline Drug Discovery and Development Research Grant Program 2003" . Retrieved March 8, 2011.
  24. ↑ "Michigan Technological University - College of Sciences and Arts" . Retrieved March 8, 2011.
  25. ↑ "Zhou Jacobi Video on Youtube".
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