Poizat Lab

Areas of Interest

More than 5 million adults have heart failure in the United States today. With an economic cost estimated at 30 billion per year, heart failure is on the rise. Heart failure can be managed by treatment with drugs but unfortunately has no cure. Our research focuses on understanding genetic and epigenetic mechanisms controlling heart failure. We use comprehensive technologies including in vitro transcription from chromatin templates, iPSC-cardiomyocytes, primary cardiomyocytes and genetically modified mice to understand intracellular signaling pathways, transcriptional regulatory networks and epigenetic events altered in the failing heart. Our long-term goal is to identify new pathways regulating this major cardiac disease to use this information for the development of therapies that will improve patients’ health.

 

    •  Epigenetic mechanisms regulating heart failure

Heart failure occurs when the heart can no longer pump blood efficiently to distribute it to the different organs of the body. One exciting ongoing area of research is on heart failure mechanisms at the “epigenetic level”. Genetic information is stored in our DNA, wrapped around histones, which form chromatin. The role of chromatin is to condense DNA in the confined space of the cell nucleus. We now know that chromatin is “fluid” and undergoes dynamic changes from an “open” to a “close” status which can turn genes “on” or “off” in specific parts of the genome. We are discovering protein complexes that are critical for the maintenance of chromatin conformation. Under stress condition, chromatin regulators can be altered, which can cause chromatin to adopt the wrong conformation and activate the wrong set of genes. This abnormal epigenetic process can lead to major cardiac pathologies such as heart failure. Our goal is to identify cardiac epigenetic factors critical for heart homeostasis and understand how their dysregulation leads to heart failure.

    • Genetic mutations causing various forms of cardiomyopathy

Heart failure can be caused by genetic mutations. We have discovered the first missense homozygous mutation in FBXO32 (also known as Atrogin-1) that causes dilated cardiomyopathy in humans by disrupting the integrity of a large protein complex named Skp1/Cul1/Fbox (SCF). Patients carrying this mutation develop advanced heart failure at a very young age. We are using CRISPR/Cas9 gene editing technology to reconstitute the mutation in human induced pluripotent stem cells (hiPSCs). hiPSCs can be re-programmed into embryonic-stem-cell like cells and then differentiated into different cell types for example cardiomyocytes. This “disease in a dish” model system allows us to compare the morphology, function and biochemical properties of the “normal” and “mutant” iPSC-cardiomyocytes, to ultimately understand how the FBXO32 mutation causes cardiomyopathy. Using this system, we can test novel or existing drugs, for their ability to prevent or reverse the cardiac defects due to the FBXO32 mutation. This is one step closer to precision medicine, an approach to patient care that is revolutionizing medicine.

 

Lab focus

  • Cardiac epigenetics
  • Genetic mutations causing dilated cardiomyopathy
  • Transcriptional assays
  • “Omics” technology
  • iPSC-cardiomyocytes to model disease

 

Achievements

  • Uncovered a novel function of CaMKII as an epigenetic enzyme by showing that CaMKII directly signals to histone H3 to remodel chromatin and activate cardiac hypertrophy.
  • Identified a novel mutation in PHC1, a member of the Polycomb group of genes, causing Primary Microcephaly by a new mechanism involving defect in cell cycle and DNA repair pathways.
  • Characterized the first mouse model deficient for a protein tyrosine phosphatase named Lmptp which revealed a protective phenotype of the knockout mice against pathological cardiac stress.
  • Discovered FBXO32 as a new cardiomyopathy gene in human. Showed that the mutation impairs the assembly of the SCF (Skp1-Cul1-F box) E3 ubiquitin ligase complex, resulting in abnormal autophagy and heart failure.

 

Education

PhD                 Ph.D. with Highest Distinction
                        Université Joseph Fourier, Grenoble, France

 

Awards & Fundings

Dr Poizat is the recipient of several awards and grants from the Philippe Foundation Inc., New York;
the American Heart Association; the Wright Foundation Research of the USC Keck School of Medicine, Los Angeles, NIH/NHLBI and King Abdulaziz City for Science and Technology (KACST), Riyadh.

Coralie Poizat, Ph.D.
Associate Professor of Biomedical Research
and Translational Medicine

Other Professional Titles
Associate Research Professor (Adjunct)
Biology Department, San Diego State University, San Diego, CA

Contact
Email:
Phone: (315) 624-7482

 

Research Interest

Dr. Poizat’s research aims at understanding molecular genetic and epigenetic changes of heart failure which remains a major cause of death worldwide.


Accomplishments

Prior to joining the Masonic Medical Research Institute, Dr Poizat was the Director of the Cardiovascular Research Program at King Faisal Specialist Hospital & Research Centre in Riyadh, a leading institution in the Middle East. Research from her laboratory contributed to the advancement of cardiovascular human genetics and to epigenetic and signaling mechanisms implicated in heart failure.


Training

A native of France, Dr Poizat obtained her Ph.D. at the University Joseph Fourier in Grenoble, France. She then joined the laboratory of Larry Kedes at the USC Keck School of Medicine in Los Angeles to pursue post-doctoral studies in molecular genetics and transcriptional regulation.


Professional Titles

  • Associate Professor, Masonic Medical Research Institute, Utica, NY
  • Adjunct Associate Research Professor, Biology Department, San Diego State University, San Diego, CA

Research Assistant

- Maya Hammonds

 

  1. Raveendran, VV, Al-Haffar, K, Kunhi, M, Belhaj, K, Al-Habeeb, W, Al-Buraiki, J et al.. Protein arginine methyltransferase 6 mediates cardiac hypertrophy by differential regulation of histone H3 arginine methylation. Heliyon. 2020;6 (5):e03864. doi: 10.1016/j.heliyon.2020.e03864. PubMed PMID:32420474 PubMed Central PMC7218648.
  2. Wade, F, Belhaj, K, Poizat, C. Protein tyrosine phosphatases in cardiac physiology and pathophysiology. Heart Fail Rev. 2018;23 (2):261-272. doi: 10.1007/s10741-018-9676-1. PubMed PMID:29396779 PubMed Central PMC5861171.
  3. Pharaon, LF, El-Orabi, NF, Kunhi, M, Al Yacoub, N, Awad, SM, Poizat, C et al.. Rosiglitazone promotes cardiac hypertrophy and alters chromatin remodeling in isolated cardiomyocytes. Toxicol Lett. 2017;280 :151-158. doi: 10.1016/j.toxlet.2017.08.011. PubMed PMID:28822817 .
  4. Al-Onazi, AS, Al-Rasheed, NM, Attia, HA, Al-Rasheed, NM, Ahmed, RM, Al-Amin, MA et al.. Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways. J Pharm Pharmacol. 2016;68 (2):219-32. doi: 10.1111/jphp.12504. PubMed PMID:26817709 .
  5. Al-Yacoub, N, Shaheen, R, Awad, SM, Kunhi, M, Dzimiri, N, Nguyen, HC et al.. FBXO32, encoding a member of the SCF complex, is mutated in dilated cardiomyopathy. Genome Biol. 2016;17 :2. doi: 10.1186/s13059-015-0861-4. PubMed PMID:26753747 PubMed Central PMC4707779.
  6. Alazami, AM, Awad, SM, Coskun, S, Al-Hassan, S, Hijazi, H, Abdulwahab, FM et al.. TLE6 mutation causes the earliest known human embryonic lethality. Genome Biol. 2015;16 :240. doi: 10.1186/s13059-015-0792-0. PubMed PMID:26537248 PubMed Central PMC4634911.
  7. Quijada, P, Hariharan, N, Cubillo, JD, Bala, KM, Emathinger, JM, Wang, BJ et al.. Nuclear Calcium/Calmodulin-dependent Protein Kinase II Signaling Enhances Cardiac Progenitor Cell Survival and Cardiac Lineage Commitment. J Biol Chem. 2015;290 (42):25411-26. doi: 10.1074/jbc.M115.657775. PubMed PMID:26324717 PubMed Central PMC4646189.
  8. Wade, F, Quijada, P, Al-Haffar, KM, Awad, SM, Kunhi, M, Toko, H et al.. Deletion of low molecular weight protein tyrosine phosphatase (Acp1) protects against stress-induced cardiomyopathy. J Pathol. 2015;237 (4):482-94. doi: 10.1002/path.4594. PubMed PMID:26213100 PubMed Central PMC5049627.
  9. Shinwari, JM, Khan, A, Awad, S, Shinwari, Z, Alaiya, A, Alanazi, M et al.. Recessive mutations in COL25A1 are a cause of congenital cranial dysinnervation disorder. Am J Hum Genet. 2015;96 (1):147-52. doi: 10.1016/j.ajhg.2014.11.006. PubMed PMID:25500261 PubMed Central PMC4289688.
  10. Awad, S, Al-Haffar, KM, Marashly, Q, Quijada, P, Kunhi, M, Al-Yacoub, N et al.. Control of histone H3 phosphorylation by CaMKIIδ in response to haemodynamic cardiac stress. J Pathol. 2015;235 (4):606-18. doi: 10.1002/path.4489. PubMed PMID:25421395 PubMed Central PMC4383650.
  11. Shareef, MA, Anwer, LA, Poizat, C. Cardiac SERCA2A/B: therapeutic targets for heart failure. Eur J Pharmacol. 2014;724 :1-8. doi: 10.1016/j.ejphar.2013.12.018. PubMed PMID:24361307 .
  12. Shaheen, R, Shamseldin, HE, Loucks, CM, Seidahmed, MZ, Ansari, S, Ibrahim Khalil, M et al.. Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans. Am J Hum Genet. 2014;94 (1):73-9. doi: 10.1016/j.ajhg.2013.11.010. PubMed PMID:24360803 PubMed Central PMC3882732.
  13. Mahmoud, SA, Poizat, C. Epigenetics and chromatin remodeling in adult cardiomyopathy. J Pathol. 2013;231 (2):147-57. doi: 10.1002/path.4234. PubMed PMID:23813473 PubMed Central PMC4285861.
  14. Awad, S, Kunhi, M, Little, GH, Bai, Y, An, W, Bers, D et al.. Nuclear CaMKII enhances histone H3 phosphorylation and remodels chromatin during cardiac hypertrophy. Nucleic Acids Res. 2013;41 (16):7656-72. doi: 10.1093/nar/gkt500. PubMed PMID:23804765 PubMed Central PMC3763528.
  15. Awad, S, Al-Dosari, MS, Al-Yacoub, N, Colak, D, Salih, MA, Alkuraya, FS et al.. Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis. Hum Mol Genet. 2013;22 (11):2200-13. doi: 10.1093/hmg/ddt072. PubMed PMID:23418308 .
  16. Innocenzi, A, Latella, L, Messina, G, Simonatto, M, Marullo, F, Berghella, L et al.. An evolutionarily acquired genotoxic response discriminates MyoD from Myf5, and differentially regulates hypaxial and epaxial myogenesis. EMBO Rep. 2011;12 (2):164-71. doi: 10.1038/embor.2010.195. PubMed PMID:21212806 PubMed Central PMC3049428.
  17. Little, GH, Saw, A, Bai, Y, Dow, J, Marjoram, P, Simkhovich, B et al.. Critical role of nuclear calcium/calmodulin-dependent protein kinase IIdeltaB in cardiomyocyte survival in cardiomyopathy. J Biol Chem. 2009;284 (37):24857-68. doi: 10.1074/jbc.M109.003186. PubMed PMID:19602725 PubMed Central PMC2757189.
  18. Little, GH, Bai, Y, Williams, T, Poizat, C. Nuclear calcium/calmodulin-dependent protein kinase IIdelta preferentially transmits signals to histone deacetylase 4 in cardiac cells. J Biol Chem. 2007;282 (10):7219-31. doi: 10.1074/jbc.M604281200. PubMed PMID:17179159 .
  19. Mao, C, Tai, WC, Bai, Y, Poizat, C, Lee, AS. In vivo regulation of Grp78/BiP transcription in the embryonic heart: role of the endoplasmic reticulum stress response element and GATA-4. J Biol Chem. 2006;281 (13):8877-87. doi: 10.1074/jbc.M505784200. PubMed PMID:16452489 .
  20. Poizat, C, Puri, PL, Bai, Y, Kedes, L. Phosphorylation-dependent degradation of p300 by doxorubicin-activated p38 mitogen-activated protein kinase in cardiac cells. Mol Cell Biol. 2005;25 (7):2673-87. doi: 10.1128/MCB.25.7.2673-2687.2005. PubMed PMID:15767673 PubMed Central PMC1061628.
  21. Kedes, L, Kloner, R, Kong, K, Poizat, C, Simkhovich, B, Iso, T et al.. New cellular and molecular approaches for the treatment of cardiac disease. Semin Nephrol. 2004;24 (5):437-40. doi: 10.1016/j.semnephrol.2004.06.010. PubMed PMID:15490406 .
  22. Simkhovich, BZ, Marjoram, P, Poizat, C, Kedes, L, Kloner, RA. Age-related changes of cardiac gene expression following myocardial ischemia/reperfusion. Arch Biochem Biophys. 2003;420 (2):268-78. doi: 10.1016/j.abb.2003.06.001. PubMed PMID:14654066 .
  23. Simkhovich, BZ, Marjoram, P, Poizat, C, Kedes, L, Kloner, RA. Brief episode of ischemia activates protective genetic program in rat heart: a gene chip study. Cardiovasc Res. 2003;59 (2):450-9. doi: 10.1016/s0008-6363(03)00399-7. PubMed PMID:12909328 .
  24. Simkhovich, BZ, Kloner, RA, Poizat, C, Marjoram, P, Kedes, LH. Gene expression profiling--a new approach in the study of myocardial ischemia. Cardiovasc Pathol. ;12 (4):180-5. doi: 10.1016/s1054-8807(03)00038-3. PubMed PMID:12826286 .
  25. Simkhovich, BZ, Abdishoo, S, Poizat, C, Hale, SL, Kedes, LH, Kloner, RA et al.. Gene activity changes in ischemically preconditioned rabbit heart gene: discovery array study. Heart Dis. ;4 (2):63-9. doi: 10.1097/00132580-200203000-00002. PubMed PMID:11975836 .
  26. Iso, T, Sartorelli, V, Poizat, C, Iezzi, S, Wu, HY, Chung, G et al.. HERP, a novel heterodimer partner of HES/E(spl) in Notch signaling. Mol Cell Biol. 2001;21 (17):6080-9. doi: 10.1128/mcb.21.17.6080-6089.2001. PubMed PMID:11486045 PubMed Central PMC87325.
  27. Poizat, C, Sartorelli, V, Chung, G, Kloner, RA, Kedes, L. Proteasome-mediated degradation of the coactivator p300 impairs cardiac transcription. Mol Cell Biol. 2000;20 (23):8643-54. doi: 10.1128/mcb.20.23.8643-8654.2000. PubMed PMID:11073966 PubMed Central PMC86467.
  28. Jeyaseelan, R, Poizat, C, Baker, RK, Abdishoo, S, Isterabadi, LB, Lyons, GE et al.. A novel cardiac-restricted target for doxorubicin. CARP, a nuclear modulator of gene expression in cardiac progenitor cells and cardiomyocytes. J Biol Chem. 1997;272 (36):22800-8. doi: 10.1074/jbc.272.36.22800. PubMed PMID:9278441 .
  29. Jeyaseelan, R, Poizat, C, Wu, HY, Kedes, L. Molecular mechanisms of doxorubicin-induced cardiomyopathy. Selective suppression of Reiske iron-sulfur protein, ADP/ATP translocase, and phosphofructokinase genes is associated with ATP depletion in rat cardiomyocytes. J Biol Chem. 1997;272 (9):5828-32. doi: 10.1074/jbc.272.9.5828. PubMed PMID:9038198 .
  30. Poizat, C, Grably, S, Cuchet, P, Keriel, C. Relationship between heart function and energy production. A study on isolated rat heart. Arch Physiol Biochem. 1996;104 (1):71-80. doi: 10.1076/apab.104.1.71.12874. PubMed PMID:8724883 .
  31. Poizat, C, Keriel, C, Cuchet, P. Is oxygen supply sufficient to induce normoxic conditions in isolated rat heart?. Basic Res Cardiol. ;89 (6):535-44. doi: 10.1007/BF00794953. PubMed PMID:7702542 .
  32. Poizat, C, Keriel, C, Garnier, A, Dubois, F, Cand, F, Cuchet, P et al.. An experimental model of hypoxia on isolated rat heart in recirculating system: study of fatty acid metabolism with an iodinated fatty acid. Arch Int Physiol Biochim Biophys. ;101 (6):347-56. doi: 10.3109/13813459309046991. PubMed PMID:7511427 .
  33. Garnier, A, Poizat, C, Keriel, C, Cuchet, P, Vork, MM, de Jong, YF et al.. Modulation of fatty acid-binding protein content of adult rat heart in response to chronic changes in plasma lipid levels. Mol Cell Biochem. ;123 (1-2):107-12. doi: 10.1007/BF01076481. PubMed PMID:8232251 .
  34. Garnier, A, Dubois, F, Keriel, C, Poizat, C, Cand, F, Cuchet, P et al.. Influence of fatty acid backdiffusion on compartmental analysis of external detection curves obtained with 123-iodohexadecenoic acid in isolated rat heart. Nucl Med Biol. 1993;20 (3):297-306. doi: 10.1016/0969-8051(93)90051-u. PubMed PMID:8485489 .
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