Ivan Moskowitz

Research Summary
The Moskowitz laboratory is devoted to the genetic, genomic and molecular study of gene regulatory networks. A single overarching theme governs work in the Moskowitz laboratory: that understanding essential gene regulatory networks will unveil the molecular logic governing biological processes, and that understanding network disruption will inform the molecular basis underlying disease. We have recently pioneered approaches to identify non-coding RNAs as markers and modulators of enhancer function (Yang and Nadadur et al, 2017). The Moskowitz laboratory has focused on two areas of cardiac biology: (1) cardiac conduction with respect to cardiac arrhythmias and (2) cardiac development with respect to Congenital Heart Disease (CHD). In cardiac development, we investigate the genetic, genomic and developmental landscape of cardiac morphogenesis. We have identified an essential role for Hedgehog signaling in the cardiac development and congenital heart disease and contributed to a paradigm shift in the understanding of cardiac septation (e.g. Hoffmann et al., 2009; Xie et al., 2012; Zhou et al., 2017). We have recently identified a surprising and novel role for Hedgehog signaling in maintaining cardiac progenitor status and preventing premature differentiation (Rowton et al., 2018). In cardiac rhythm, we investigate the molecular mechanisms underlying the genetic basis of cardiac arrhythmias. We have defined the first molecular networks and linking GWAS loci in cardiac conduction (Arnolds et al, 2012), the first molecular network in Atrial Fibrillation, the most common arrhythmia world-wide (Nadadur et al., 2016) and the functional genomic mechanisms underlying genetic associations (Van den Boogaard et al., 2014).
Keywords
Genetics, Molecular, Genetics, Genomics, Developmental Biology, Developmental Gene Expression Regulation, Transcriptional Regulatory Elements, Heart Development, Congenital Heart Disease, Cardiac Rhythm, Cardiac Arrhythmias
Education
  • Harvard Medical School, Boston, MA, Fellowship Genetics 06/2006
  • Children's Hospital, Boston, MA, Fellowship Congenital Heart Disease 06/2001
  • Brigham and Women’s Hospital, Boston, MA , Residency Pathology 06/2000
  • University of Wisconsin, School of Medicine, Madison, WI, M.D./Ph.D. Biochemistry 06/1998
  • Marine Biological Laboratory, Woods Hole, MA, Embryology 06/1994
  • Wesleyan University, Middletown, CT, B.A. Biochemistry/Molecular Biology 06/1988
Awards & Honors
  • 2006 - Louis N. and Arnold M. Katz Basic Research Prize American Heart Association
  • 2013 - Established Investigator Award American Heart Association
  • 2014 - American Society of Clinical Investigation American Society of Clinical Investigation
  • 2015 - Fellow of the American Heart Association American Heart Association
Publications
  1. Dai W, Laforest B, Tyan L, Shen KM, Nadadur RD, Alvarado FJ, Mazurek SR, Lazarevic S, Gadek M, Wang Y, Li Y, Valdivia HH, Shen L, Broman MT, Moskowitz IP, Weber CR. A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice. Elife. 2019 Mar 21; 8. View in: PubMed

  2. Krause MD, Huang RT, Wu D, Shentu TP, Harrison DL, Whalen MB, Stolze LK, Di Rienzo A, Moskowitz IP, Civelek M, Romanoski CE, Fang Y. Genetic variant at coronary artery disease and ischemic stroke locus 1p32.2 regulates endothelial responses to hemodynamics. Proc Natl Acad Sci U S A. 2018 11 27; 115(48):E11349-E11358. View in: PubMed

  3. Steimle JD, Rankin SA, Slagle CE, Bekeny J, Rydeen AB, Chan SS, Kweon J, Yang XH, Ikegami K, Nadadur RD, Rowton M, Hoffmann AD, Lazarevic S, Thomas W, Boyle Anderson EAT, Horb ME, Luna-Zurita L, Ho RK, Kyba M, Jensen B, Zorn AM, Conlon FL, Moskowitz IP. Evolutionarily conserved Tbx5-Wnt2/2b pathway orchestrates cardiopulmonary development. Proc Natl Acad Sci U S A. 2018 11 06; 115(45):E10615-E10624. View in: PubMed

  4. Singh BN, Koyano-Nakagawa N, Gong W, Moskowitz IP, Weaver CV, Braunlin E, Das S, van Berlo JH, Garry MG, Garry DJ. A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human. Nat Commun. 2018 10 12; 9(1):4237. View in: PubMed

  5. Montefiori LE, Sobreira DR, Sakabe NJ, Aneas I, Joslin AC, Hansen GT, Bozek G, Moskowitz IP, McNally EM, Nóbrega MA. A promoter interaction map for cardiovascular disease genetics. Elife. 2018 07 10; 7. View in: PubMed

  6. Musunuru K, Bernstein D, Cole FS, Khokha MK, Lee FS, Lin S, McDonald TV, Moskowitz IP, Quertermous T, Sankaran VG, Schwartz DA, Silverman EK, Zhou X, Hasan AAK, Luo XJ. Functional Assays to Screen and Dissect Genomic Hits: Doubling Down on the National Investment in Genomic Research. Circ Genom Precis Med. 2018 04; 11(4):e002178. View in: PubMed

  7. Yang XH, Nadadur RD, Hilvering CR, Bianchi V, Werner M, Mazurek SR, Gadek M, Shen KM, Goldman JA, Tyan L, Bekeny J, Hall JM, Lee N, Perez-Cervantes C, Burnicka-Turek O, Poss KD, Weber CR, de Laat W, Ruthenburg AJ, Moskowitz IP. Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm. Elife. 2017 12 27; 6. View in: PubMed

  8. Werner MS, Sullivan MA, Shah RN, Nadadur RD, Grzybowski AT, Galat V, Moskowitz IP, Ruthenburg AJ. Chromatin-enriched lncRNAs can act as cell-type specific activators of proximal gene transcription. Nat Struct Mol Biol. 2017 Jul; 24(7):596-603. View in: PubMed

  9. Zhou L, Liu J, Xiang M, Olson P, Guzzetta A, Zhang K, Moskowitz IP, Xie L. Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation. Proc Natl Acad Sci U S A. 2017 02 21; 114(8):E1422-E1431. View in: PubMed

  10. Steimle JD, Moskowitz IP. TBX5: A Key Regulator of Heart Development. Curr Top Dev Biol. 2017; 122:195-221. View in: PubMed

  11. Hoffmann AD, Yang XH, Burnicka-Turek O, Bosman JD, Ren X, Xie L, Steimle JD, Vokes SA, McMahon AP, Kalinichenko VV, Moskowitz IP. Correction: Foxf Genes Integrate Tbx5 and Hedgehog Pathways in the Second Heart Field for Cardiac Septation. PLoS Genet. 2016 Dec; 12(12):e1006533. View in: PubMed

  12. Nadadur RD, Broman MT, Boukens B, Mazurek SR, Yang X, van den Boogaard M, Bekeny J, Gadek M, Ward T, Zhang M, Qiao Y, Martin JF, Seidman CE, Seidman J, Christoffels V, Efimov IR, McNally EM, Weber CR, Moskowitz IP. Pitx2 modulates a Tbx5-dependent gene regulatory network to maintain atrial rhythm. Sci Transl Med. 2016 08 31; 8(354):354ra115. View in: PubMed

  13. Burnicka-Turek O, Steimle JD, Huang W, Felker L, Kamp A, Kweon J, Peterson M, Reeves RH, Maslen CL, Gruber PJ, Yang XH, Shendure J, Moskowitz IP. Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms. Hum Mol Genet. 2016 07 15; 25(14):3011-3028. View in: PubMed

  14. Priest JR, Osoegawa K, Mohammed N, Nanda V, Kundu R, Schultz K, Lammer EJ, Girirajan S, Scheetz T, Waggott D, Haddad F, Reddy S, Bernstein D, Burns T, Steimle JD, Yang XH, Moskowitz IP, Hurles M, Lifton RP, Nickerson D, Bamshad M, Eichler EE, Mital S, Sheffield V, Quertermous T, Gelb BD, Portman M, Ashley EA. De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects. PLoS Genet. 2016 Apr; 12(4):e1005963. View in: PubMed

  15. Waldron L, Steimle JD, Greco TM, Gomez NC, Dorr KM, Kweon J, Temple B, Yang XH, Wilczewski CM, Davis IJ, Cristea IM, Moskowitz IP, Conlon FL. The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation. Dev Cell. 2016 Feb 08; 36(3):262-75. View in: PubMed

  16. Rowton M, Moskowitz IP. Many ways to break a heart. Elife. 2015 Aug 25; 4. View in: PubMed

  17. Polk RC, Gergics P, Steimle JD, Li H, Moskowitz IP, Camper SA, Reeves RH. The pattern of congenital heart defects arising from reduced Tbx5 expression is altered in a Down syndrome mouse model. BMC Dev Biol. 2015 Jul 25; 15:30. View in: PubMed

  18. Shamis Y, Cullen DE, Liu L, Yang G, Ng SF, Xiao L, Bell FT, Ray C, Takikawa S, Moskowitz IP, Cai CL, Yang X, Li X. Maternal and zygotic Zfp57 modulate NOTCH signaling in cardiac development. Proc Natl Acad Sci U S A. 2015 Apr 21; 112(16):E2020-9. View in: PubMed

  19. Quintero-Rivera F, Xi QJ, Keppler-Noreuil KM, Lee JH, Higgins AW, Anchan RM, Roberts AE, Seong IS, Fan X, Lage K, Lu LY, Tao J, Hu X, Berezney R, Gelb BD, Kamp A, Moskowitz IP, Lacro RV, Lu W, Morton CC, Gusella JF, Maas RL. MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus. Hum Mol Genet. 2015 Apr 15; 24(8):2375-89. View in: PubMed

  20. Hoffmann AD, Yang XH, Burnicka-Turek O, Bosman JD, Ren X, Steimle JD, Vokes SA, McMahon AP, Kalinichenko VV, Moskowitz IP. Foxf genes integrate tbx5 and hedgehog pathways in the second heart field for cardiac septation. PLoS Genet. 2014 Oct; 10(10):e1004604. View in: PubMed

  21. van den Boogaard M, Smemo S, Burnicka-Turek O, Arnolds DE, van de Werken HJ, Klous P, McKean D, Muehlschlegel JD, Moosmann J, Toka O, Yang XH, Koopmann TT, Adriaens ME, Bezzina CR, de Laat W, Seidman C, Seidman JG, Christoffels VM, Nobrega MA, Barnett P, Moskowitz IP. A common genetic variant within SCN10A modulates cardiac SCN5A expression. J Clin Invest. 2014 Apr; 124(4):1844-52. View in: PubMed

  22. Xie L, Hoffmann AD, Burnicka-Turek O, Friedland-Little JM, Zhang K, Moskowitz IP. Tbx5-hedgehog molecular networks are essential in the second heart field for atrial septation. Dev Cell. 2012 Aug 14; 23(2):280-91. View in: PubMed

  23. Arnolds DE, Liu F, Fahrenbach JP, Kim GH, Schillinger KJ, Smemo S, McNally EM, Nobrega MA, Patel VV, Moskowitz IP. TBX5 drives Scn5a expression to regulate cardiac conduction system function. J Clin Invest. 2012 Jul; 122(7):2509-18. View in: PubMed

  24. Smemo S, Campos LC, Moskowitz IP, Krieger JE, Pereira AC, Nobrega MA. Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease. Hum Mol Genet. 2012 Jul 15; 21(14):3255-63. View in: PubMed

  25. Kim EY, Chen L, Ma Y, Yu W, Chang J, Moskowitz IP, Wang J. Enhanced desumoylation in murine hearts by overexpressed SENP2 leads to congenital heart defects and cardiac dysfunction. J Mol Cell Cardiol. 2012 Mar; 52(3):638-49. View in: PubMed

  26. Kim EY, Chen L, Ma Y, Yu W, Chang J, Moskowitz IP, Wang J. Expression of sumoylation deficient Nkx2.5 mutant in Nkx2.5 haploinsufficient mice leads to congenital heart defects. PLoS One. 2011; 6(6):e20803. View in: PubMed

  27. Friedland-Little JM, Hoffmann AD, Ocbina PJ, Peterson MA, Bosman JD, Chen Y, Cheng SY, Anderson KV, Moskowitz IP. A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus. Hum Mol Genet. 2011 Oct 01; 20(19):3725-37. View in: PubMed

  28. Wang J, Chen L, Wen S, Zhu H, Yu W, Moskowitz IP, Shaw GM, Finnell RH, Schwartz RJ. Defective sumoylation pathway directs congenital heart disease. Birth Defects Res A Clin Mol Teratol. 2011 Jun; 91(6):468-76. View in: PubMed

  29. Ocbina PJ, Eggenschwiler JT, Moskowitz I, Anderson KV. Complex interactions between genes controlling trafficking in primary cilia. Nat Genet. 2011 Jun; 43(6):547-53. View in: PubMed

  30. Arnolds DE, Chu A, McNally EM, Nobrega MA, Moskowitz IP. The emerging genetic landscape underlying cardiac conduction system function. Birth Defects Res A Clin Mol Teratol. 2011 Jun; 91(6):578-85. View in: PubMed

  31. Arnolds DE, Moskowitz IP. Inducible recombination in the cardiac conduction system of minK: CreERT² BAC transgenic mice. Genesis. 2011 Nov; 49(11):878-84. View in: PubMed

  32. Moskowitz IP, Wang J, Peterson MA, Pu WT, Mackinnon AC, Oxburgh L, Chu GC, Sarkar M, Berul C, Smoot L, Robertson EJ, Schwartz R, Seidman JG, Seidman CE. Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development. [corrected] Proc Natl Acad Sci U S A. 2011 Mar 08; 108(10):4006-11. View in: PubMed

  33. Shah MY, Vasanthakumar A, Barnes NY, Figueroa ME, Kamp A, Hendrick C, Ostler KR, Davis EM, Lin S, Anastasi J, Le Beau MM, Moskowitz IP, Melnick A, Pytel P, Godley LA. DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis. Cancer Res. 2010 Jul 15; 70(14):5840-50. View in: PubMed

  34. Kamp A, Peterson MA, Svenson KL, Bjork BC, Hentges KE, Rajapaksha TW, Moran J, Justice MJ, Seidman JG, Seidman CE, Moskowitz IP, Beier DR. Genome-wide identification of mouse congenital heart disease loci. Hum Mol Genet. 2010 Aug 15; 19(16):3105-13. View in: PubMed

  35. Dellefave LM, Pytel P, Mewborn S, Mora B, Guris DL, Fedson S, Waggoner D, Moskowitz I, McNally EM. Sarcomere mutations in cardiomyopathy with left ventricular hypertrabeculation. Circ Cardiovasc Genet. 2009 Oct; 2(5):442-9. View in: PubMed

  36. Hoffmann AD, Peterson MA, Friedland-Little JM, Anderson SA, Moskowitz IP. sonic hedgehog is required in pulmonary endoderm for atrial septation. Development. 2009 May; 136(10):1761-70. View in: PubMed

  37. Boles MK, Wilkinson BM, Maxwell A, Lai L, Mills AA, Nishijima I, Salinger AP, Moskowitz I, Hirschi KK, Liu B, Bradley A, Justice MJ. A mouse chromosome 4 balancer ENU-mutagenesis screen isolates eleven lethal lines. BMC Genet. 2009 Mar 06; 10:12. View in: PubMed

  38. King JC, Moskowitz IP, Burgon PG, Ahmad F, Stone JR, Seidman JG, Lees JA. E2F3 plays an essential role in cardiac development and function. Cell Cycle. 2008 Dec; 7(23):3775-80. View in: PubMed

  39. Pytel P, Husain A, Moskowitz I, Raman J, MacLeod H, Anderson AS, Burke M, McNally EM. Ventricular fibrillation following autologous intramyocardial cell therapy for inherited cardiomyopathy. Cardiovasc Pathol. 2010 Mar-Apr; 19(2):e33-6. View in: PubMed

  40. Ahmad F, Banerjee SK, Lage ML, Huang XN, Smith SH, Saba S, Rager J, Conner DA, Janczewski AM, Tobita K, Tinney JP, Moskowitz IP, Perez-Atayde AR, Keller BB, Mathier MA, Shroff SG, Seidman CE, Seidman JG. The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy. PLoS One. 2008 Jul 09; 3(7):e2642. View in: PubMed

  41. Moskowitz IP, Kim JB, Moore ML, Wolf CM, Peterson MA, Shendure J, Nobrega MA, Yokota Y, Berul C, Izumo S, Seidman JG, Seidman CE. A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development. Cell. 2007 Jun 29; 129(7):1365-76. View in: PubMed

  42. Viswanathan S, Burch JB, Fishman GI, Moskowitz IP, Benson DW. Characterization of sinoatrial node in four conduction system marker mice. J Mol Cell Cardiol. 2007 May; 42(5):946-53. View in: PubMed

  43. Stroud DM, Darrow BJ, Kim SD, Zhang J, Jongbloed MR, Rentschler S, Moskowitz IP, Seidman J, Fishman GI. Complex genomic rearrangement in CCS-LacZ transgenic mice. Genesis. 2007 Feb; 45(2):76-82. View in: PubMed

  44. Feng Y, Chen MH, Moskowitz IP, Mendonza AM, Vidali L, Nakamura F, Kwiatkowski DJ, Walsh CA. Filamin A (FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis. Proc Natl Acad Sci U S A. 2006 Dec 26; 103(52):19836-41. View in: PubMed

  45. Aru GM, Juraszek A, Moskowitz I, Van Praagh R. Tetralogy of Fallot with congenital aortic valvar stenosis: the tetralogy-truncus interrelationship. Pediatr Cardiol. 2006 May-Jun; 27(3):354-9. View in: PubMed

  46. Wolf CM, Moskowitz IP, Arno S, Branco DM, Semsarian C, Bernstein SA, Peterson M, Maida M, Morley GE, Fishman G, Berul CI, Seidman CE, Seidman JG. Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia. Proc Natl Acad Sci U S A. 2005 Dec 13; 102(50):18123-8. View in: PubMed

  47. Kontani K, Moskowitz IP, Rothman JH. Repression of cell-cell fusion by components of the C. elegans vacuolar ATPase complex. Dev Cell. 2005 May; 8(5):787-94. View in: PubMed

  48. Moskowitz IP, Pizard A, Patel VV, Bruneau BG, Kim JB, Kupershmidt S, Roden D, Berul CI, Seidman CE, Seidman JG. The T-Box transcription factor Tbx5 is required for the patterning and maturation of the murine cardiac conduction system. Development. 2004 Aug; 131(16):4107-16. View in: PubMed

  49. Wakimoto H, Kasahara H, Maguire CT, Moskowitz IP, Izumo S, Berul CI. Cardiac electrophysiological phenotypes in postnatal expression of Nkx2.5 transgenic mice. Genesis. 2003 Nov; 37(3):144-50. View in: PubMed

  50. FOX MJ, MOSKOWITZ I. Hysteria in poliomyelitis. Wis Med J. 1953 Jun; 52(6):313-6. View in: PubMed

  51. Patel VV, Arad M, Moskowitz IP, Maguire CT, Branco D, Seidman JG, Seidman CE, Berul CI. Electrophysiologic characterization and postnatal development of ventricular pre-excitation in a mouse model of cardiac hypertrophy and Wolff-Parkinson-White syndrome. J Am Coll Cardiol. 2003 Sep 03; 42(5):942-51. View in: PubMed

  52. Arad M, Moskowitz IP, Patel VV, Ahmad F, Perez-Atayde AR, Sawyer DB, Walter M, Li GH, Burgon PG, Maguire CT, Stapleton D, Schmitt JP, Guo XX, Pizard A, Kupershmidt S, Roden DM, Berul CI, Seidman CE, Seidman JG. Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy. Circulation. 2003 Jun 10; 107(22):2850-6. View in: PubMed

  53. Laufs H, Nigrovic PA, Schneider LC, Oettgen H, Del NP, Moskowitz IP, Blume E, Perez-Atayde AR. Giant cell myocarditis in a 12-year-old girl with common variable immunodeficiency. Mayo Clin Proc. 2002 Jan; 77(1):92-6. View in: PubMed

  54. Berul CI, McConnell BK, Wakimoto H, Moskowitz IP, Maguire CT, Semsarian C, Vargas MM, Gehrmann J, Seidman CE, Seidman JG. Ventricular arrhythmia vulnerability in cardiomyopathic mice with homozygous mutant Myosin-binding protein C gene. Circulation. 2001 Nov 27; 104(22):2734-9. View in: PubMed

  55. McConnell BK, Fatkin D, Semsarian C, Jones KA, Georgakopoulos D, Maguire CT, Healey MJ, Mudd JO, Moskowitz IP, Conner DA, Giewat M, Wakimoto H, Berul CI, Schoen FJ, Kass DA, Seidman CE, Seidman JG. Comparison of two murine models of familial hypertrophic cardiomyopathy. Circ Res. 2001 Mar 02; 88(4):383-9. View in: PubMed

  56. Moskowitz IP, Gaynon PS, Shahidi NT, Cripe TP. Low-dose cyclosporin A therapy in children with refractory immune thrombocytopenic purpura. J Pediatr Hematol Oncol. 1999 Jan-Feb; 21(1):77-9. View in: PubMed

  57. Moskowitz IP, Rothman JH. lin-12 and glp-1 are required zygotically for early embryonic cellular interactions and are regulated by maternal GLP-1 signaling in Caenorhabditis elegans. Development. 1996 Dec; 122(12):4105-17. View in: PubMed

  58. Gendreau SB, Moskowitz IP, Terns RM, Rothman JH. The potential to differentiate epidermis is unequally distributed in the AB lineage during early embryonic development in C. elegans. Dev Biol. 1994 Dec; 166(2):770-81. View in: PubMed

  59. Moskowitz IP, Gendreau SB, Rothman JH. Combinatorial specification of blastomere identity by glp-1-dependent cellular interactions in the nematode Caenorhabditis elegans. Development. 1994 Nov; 120(11):3325-38. View in: PubMed

  60. Moskowitz IP, Heichman KA, Johnson RC. Alignment of recombination sites in Hin-mediated site-specific DNA recombination. Genes Dev. 1991 Sep; 5(9):1635-45. View in: PubMed

  61. Heichman KA, Moskowitz IP, Johnson RC. Configuration of DNA strands and mechanism of strand exchange in the Hin invertasome as revealed by analysis of recombinant knots. Genes Dev. 1991 Sep; 5(9):1622-34. View in: PubMed