Marcelo A. Nobrega

Research Summary
We are interested in mechanistically deciphering how genetic variation increase the risk of human diseases. We are particularly interested in understanding how noncoding genetic variants, most uncovered by Genome-wide Association Studies are associated with disease etiology. The underlying assumption is that a majority of these variants impart their effects by altering the quantitative, temporal, and/or spatial properties of long-range cis-regulatory enhancers. Several challenges hinder the mechanistically follow-up of these GWAS, including 1) identification of the causal variant(s) associated with the disease trait, 2) characterization of the spatial and temporal properties of the enhancer(s) harboring the causal variant(s), 3) establishing differential regulatory properties of the allelic variants of the enhancer(s), 4) identification of the causal gene(s) connected with the enhancer(s) of interest, and 5) characterization of the molecular, cellular, and systems-level phenotypes associated with mis-regulation of the target gene(s). Our lab has been developing pipelines to tackle all these challenges, resulting in integrated experimental and computational strategies to uncover the mechanisms linking regulatory variants to human disease.
Biosciences Graduate Program Association
Publications
  1. van Ouwerkerk AF, Bosada FM, van Duijvenboden K, Hill MC, Montefiori LE, Scholman KT, Liu J, de Vries AAF, Boukens BJ, Ellinor PT, Goumans MJTH, Efimov IR, Nobrega MA, Barnett P, Martin JF, Christoffels VM. Identification of atrial fibrillation associated genes and functional non-coding variants. Nat Commun. 2019 Oct 18; 10(1):4755. View in: PubMed

  2. Montefiori LE, Nobrega MA. Gene therapy for pathologic gene expression. Science. 2019 01 18; 363(6424):231-232. View in: PubMed

  3. Srivastava R, Rolyan H, Xie Y, Li N, Bhat N, Hong L, Esteghamat F, Adeniran A, Geirsson A, Zhang J, Ge G, Nobrega M, Martin KA, Mani A. TCF7L2 (Transcription Factor 7-Like 2) Regulation of GATA6 (GATA-Binding Protein 6)-Dependent and -Independent Vascular Smooth Muscle Cell Plasticity and Intimal Hyperplasia. Arterioscler Thromb Vasc Biol. 2019 02; 39(2):250-262. View in: PubMed

  4. 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

  5. Boogerd CJ, Zhu X, Aneas I, Sakabe N, Zhang L, Sobreira DR, Montefiori L, Bogomolovas J, Joslin AC, Zhou B, Chen J, Nobrega MA, Evans SM. Tbx20 Is Required in Mid-Gestation Cardiomyocytes and Plays a Central Role in Atrial Development. Circ Res. 2018 08 03; 123(4):428-442. View in: PubMed

  6. Montefiori L, Hernandez L, Zhang Z, Gilad Y, Ober C, Crawford G, Nobrega M, Jo Sakabe N. Reducing mitochondrial reads in ATAC-seq using CRISPR/Cas9. Sci Rep. 2017 05 26; 7(1):2451. View in: PubMed

  7. Nicodemus-Johnson J, Myers RA, Sakabe NJ, Sobreira DR, Hogarth DK, Naureckas ET, Sperling AI, Solway J, White SR, Nobrega MA, Nicolae DL, Gilad Y, Ober C. DNA methylation in lung cells is associated with asthma endotypes and genetic risk. JCI Insight. 2016 12 08; 1(20):e90151. View in: PubMed

  8. Nóbrega MA, Gómez-Skarmeta JL. Editorial. Semin Cell Dev Biol. 2016 09; 57:1. View in: PubMed

  9. Boogerd CJ, Aneas I, Sakabe N, Dirschinger RJ, Cheng QJ, Zhou B, Chen J, Nobrega MA, Evans SM. Probing chromatin landscape reveals roles of endocardial TBX20 in septation. J Clin Invest. 2016 08 01; 126(8):3023-35. View in: PubMed

  10. Gómez-Marín C, Tena JJ, Acemel RD, López-Mayorga M, Naranjo S, de la Calle-Mustienes E, Maeso I, Beccari L, Aneas I, Vielmas E, Bovolenta P, Nobrega MA, Carvajal J, Gómez-Skarmeta JL. Evolutionary comparison reveals that diverging CTCF sites are signatures of ancestral topological associating domains borders. Proc Natl Acad Sci U S A. 2015 Jun 16; 112(24):7542-7. View in: PubMed

  11. Guimarães-Camboa N, Stowe J, Aneas I, Sakabe N, Cattaneo P, Henderson L, Kilberg MS, Johnson RS, Chen J, McCulloch AD, Nobrega MA, Evans SM, Zambon AC. HIF1a Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes. Dev Cell. 2015 Jun 08; 33(5):507-21. View in: PubMed

  12. Janissen R, Murillo DM, Niza B, Sahoo PK, Nobrega MM, Cesar CL, Temperini ML, Carvalho HF, de Souza AA, Cotta MA. Spatiotemporal distribution of different extracellular polymeric substances and filamentation mediate Xylella fastidiosa adhesion and biofilm formation. Sci Rep. 2015 Apr 20; 5:9856. View in: PubMed

  13. Chapman KM, Medrano GA, Jaichander P, Chaudhary J, Waits AE, Nobrega MA, Hotaling JM, Ober C, Hamra FK. Targeted Germline Modifications in Rats Using CRISPR/Cas9 and Spermatogonial Stem Cells. Cell Rep. 2015 Mar 24; 10(11):1828-35. View in: PubMed

  14. Mutskov V, Khalyfa A, Wang Y, Carreras A, Nobrega MA, Gozal D. Early-life physical activity reverses metabolic and Foxo1 epigenetic misregulation induced by gestational sleep disturbance. Am J Physiol Regul Integr Comp Physiol. 2015 Mar 01; 308(5):R419-30. View in: PubMed

  15. Bailey KA, Savic D, Zielinski M, Park SY, Wang LJ, Witkowski P, Brady M, Hara M, Bell GI, Nobrega MA. Evidence of non-pancreatic beta cell-dependent roles of Tcf7l2 in the regulation of glucose metabolism in mice. Hum Mol Genet. 2015 Mar 15; 24(6):1646-54. View in: PubMed

  16. Ferrara AM, Pappa T, Fu J, Brown CD, Peterson A, Moeller LC, Wyne K, White KP, Pluzhnikov A, Trubetskoy V, Nobrega M, Weiss RE, Dumitrescu AM, Refetoff S. A novel mechanism of inherited TBG deficiency: mutation in a liver-specific enhancer. J Clin Endocrinol Metab. 2015 Jan; 100(1):E173-81. View in: PubMed

  17. Zhou Y, Park SY, Su J, Bailey K, Ottosson-Laakso E, Shcherbina L, Oskolkov N, Zhang E, Thevenin T, Fadista J, Bennet H, Vikman P, Wierup N, Fex M, Rung J, Wollheim C, Nobrega M, Renström E, Groop L, Hansson O. TCF7L2 is a master regulator of insulin production and processing. Hum Mol Genet. 2014 Dec 15; 23(24):6419-31. View in: PubMed

  18. 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

  19. Zhou J, Wu J, Li B, Liu D, Yu J, Yan X, Zheng S, Wang J, Zhang L, Zhang L, He F, Li Q, Chen A, Zhang Y, Zhao X, Guan Y, Zhao X, Yan J, Ni J, Nobrega MA, Löwenberg B, Delwel R, Valk PJ, Kumar A, Xie L, Tenen DG, Huang G, Wang QF. PU.1 is essential for MLL leukemia partially via crosstalk with the MEIS/HOX pathway. Leukemia. 2014 Jul; 28(7):1436-48. View in: PubMed

  20. Sakabe NJ, Nobrega MA. Beyond the ENCODE project: using genomics and epigenomics strategies to study enhancer evolution. Philos Trans R Soc Lond B Biol Sci. 2013 Dec 19; 368(1632):20130022. View in: PubMed

  21. Wang QF, Li YJ, Dong JF, Li B, Kaberlein JJ, Zhang L, Arimura FE, Luo RT, Ni J, He F, Wu J, Mattison R, Zhou J, Wang CZ, Prabhakar S, Nobrega MA, Thirman MJ. Regulation of MEIS1 by distal enhancer elements in acute leukemia. Leukemia. 2014 Jan; 28(1):138-46. View in: PubMed

  22. Fu Y, Jia G, Pang X, Wang RN, Wang X, Li CJ, Smemo S, Dai Q, Bailey KA, Nobrega MA, Han KL, Cui Q, He C. FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA. Nat Commun. 2013; 4:1798. View in: PubMed

  23. Pennacchio LA, Bickmore W, Dean A, Nobrega MA, Bejerano G. Enhancers: five essential questions. Nat Rev Genet. 2013 04; 14(4):288-95. View in: PubMed

  24. Nobrega MA. TCF7L2 and glucose metabolism: time to look beyond the pancreas. Diabetes. 2013 Mar; 62(3):706-8. View in: PubMed

  25. Savic D, Park SY, Bailey KA, Bell GI, Nobrega MA. In vitro scan for enhancers at the TCF7L2 locus. Diabetologia. 2013 Jan; 56(1):121-5. View in: PubMed

  26. 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

  27. Savic D, Bell GI, Nobrega MA. An in vivo cis-regulatory screen at the type 2 diabetes associated TCF7L2 locus identifies multiple tissue-specific enhancers. PLoS One. 2012; 7(5):e36501. View in: PubMed

  28. Distler MG, Plant LD, Sokoloff G, Hawk AJ, Aneas I, Wuenschell GE, Termini J, Meredith SC, Nobrega MA, Palmer AA. Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal. J Clin Invest. 2012 Jun; 122(6):2306-15. View in: PubMed

  29. 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

  30. Auton A, Fledel-Alon A, Pfeifer S, Venn O, Ségurel L, Street T, Leffler EM, Bowden R, Aneas I, Broxholme J, Humburg P, Iqbal Z, Lunter G, Maller J, Hernandez RD, Melton C, Venkat A, Nobrega MA, Bontrop R, Myers S, Donnelly P, Przeworski M, McVean G. A fine-scale chimpanzee genetic map from population sequencing. Science. 2012 Apr 13; 336(6078):193-8. View in: PubMed

  31. Sakabe NJ, Aneas I, Shen T, Shokri L, Park SY, Bulyk ML, Evans SM, Nobrega MA. Dual transcriptional activator and repressor roles of TBX20 regulate adult cardiac structure and function. Hum Mol Genet. 2012 May 15; 21(10):2194-204. View in: PubMed

  32. Sakabe NJ, Savic D, Nobrega MA. Transcriptional enhancers in development and disease. Genome Biol. 2012 Jan 23; 13(1):238. View in: PubMed

  33. Shen T, Aneas I, Sakabe N, Dirschinger RJ, Wang G, Smemo S, Westlund JM, Cheng H, Dalton N, Gu Y, Boogerd CJ, Cai CL, Peterson K, Chen J, Nobrega MA, Evans SM. Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function. J Clin Invest. 2011 Dec; 121(12):4640-54. View in: PubMed

  34. Savic D, Distler MG, Sokoloff G, Shanahan NA, Dulawa SC, Palmer AA, Nobrega MA. Modulation ofTcf7l2 expression alters behavior in mice. PLoS One. 2011; 6(10):e26897. View in: PubMed

  35. Schneider I, Aneas I, Gehrke AR, Dahn RD, Nobrega MA, Shubin NH. Appendage expression driven by the Hoxd Global Control Region is an ancient gnathostome feature. Proc Natl Acad Sci U S A. 2011 Aug 02; 108(31):12782-6. View in: PubMed

  36. Savic D, Ye H, Aneas I, Park SY, Bell GI, Nobrega MA. Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism. Genome Res. 2011 Sep; 21(9):1417-25. View in: PubMed

  37. Taher L, McGaughey DM, Maragh S, Aneas I, Bessling SL, Miller W, Nobrega MA, McCallion AS, Ovcharenko I. Genome-wide identification of conserved regulatory function in diverged sequences. Genome Res. 2011 Jul; 21(7):1139-49. View in: PubMed

  38. 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

  39. Sakabe NJ, Nobrega MA. Genome-wide maps of transcription regulatory elements. Wiley Interdiscip Rev Syst Biol Med. 2010 Jul-Aug; 2(4):422-437. View in: PubMed

  40. Wasserman NF, Aneas I, Nobrega MA. An 8q24 gene desert variant associated with prostate cancer risk confers differential in vivo activity to a MYC enhancer. Genome Res. 2010 Sep; 20(9):1191-7. View in: PubMed

  41. Nobrega MA. Journal club. A human geneticist explores the ways that genes are regulated. Nature. 2010 Jul 01; 466(7302):11. View in: PubMed

  42. Gotea V, Visel A, Westlund JM, Nobrega MA, Pennacchio LA, Ovcharenko I. Homotypic clusters of transcription factor binding sites are a key component of human promoters and enhancers. Genome Res. 2010 May; 20(5):565-77. View in: PubMed

  43. Castillo HA, Cravo RM, Azambuja AP, Simões-Costa MS, Sura-Trueba S, Gonzalez J, Slonimsky E, Almeida K, Abreu JG, de Almeida MA, Sobreira TP, de Oliveira SH, de Oliveira PS, Signore IA, Colombo A, Concha ML, Spengler TS, Bronner-Fraser M, Nobrega M, Rosenthal N, Xavier-Neto J. Insights into the organization of dorsal spinal cord pathways from an evolutionarily conserved raldh2 intronic enhancer. Development. 2010 Feb; 137(3):507-18. View in: PubMed

  44. Narlikar L, Sakabe NJ, Blanski AA, Arimura FE, Westlund JM, Nobrega MA, Ovcharenko I. Genome-wide discovery of human heart enhancers. Genome Res. 2010 Mar; 20(3):381-92. View in: PubMed

  45. Nobrega MA, Solberg Woods LC, Fleming S, Jacob HJ. Distinct genetic regulation of progression of diabetes and renal disease in the Goto-Kakizaki rat. Physiol Genomics. 2009 Sep 09; 39(1):38-46. View in: PubMed

  46. van Bon BW, Mefford HC, Menten B, Koolen DA, Sharp AJ, Nillesen WM, Innis JW, de Ravel TJ, Mercer CL, Fichera M, Stewart H, Connell LE, Ounap K, Lachlan K, Castle B, Van der Aa N, van Ravenswaaij C, Nobrega MA, Serra-Juhé C, Simonic I, de Leeuw N, Pfundt R, Bongers EM, Baker C, Finnemore P, Huang S, Maloney VK, Crolla JA, van Kalmthout M, Elia M, Vandeweyer G, Fryns JP, Janssens S, Foulds N, Reitano S, Smith K, Parkel S, Loeys B, Woods CG, Oostra A, Speleman F, Pereira AC, Kurg A, Willatt L, Knight SJ, Vermeesch JR, Romano C, Barber JC, Mortier G, Pérez-Jurado LA, Kooy F, Brunner HG, Eichler EE, Kleefstra T, de Vries BB. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet. 2009 Aug; 46(8):511-23. View in: PubMed

  47. 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

  48. Pennacchio LA, Loots GG, Nobrega MA, Ovcharenko I. Predicting tissue-specific enhancers in the human genome. Genome Res. 2007 Feb; 17(2):201-11. View in: PubMed

  49. Pennacchio LA, Ahituv N, Moses AM, Prabhakar S, Nobrega MA, Shoukry M, Minovitsky S, Dubchak I, Holt A, Lewis KD, Plajzer-Frick I, Akiyama J, De Val S, Afzal V, Black BL, Couronne O, Eisen MB, Visel A, Rubin EM. In vivo enhancer analysis of human conserved non-coding sequences. Nature. 2006 Nov 23; 444(7118):499-502. View in: PubMed

  50. Ovcharenko I, Nobrega MA. Identifying synonymous regulatory elements in vertebrate genomes. Nucleic Acids Res. 2005 Jul 01; 33(Web Server issue):W403-7. View in: PubMed

  51. Poulin F, Nobrega MA, Plajzer-Frick I, Holt A, Afzal V, Rubin EM, Pennacchio LA. In vivo characterization of a vertebrate ultraconserved enhancer. Genomics. 2005 Jun; 85(6):774-81. View in: PubMed

  52. Ovcharenko I, Loots GG, Nobrega MA, Hardison RC, Miller W, Stubbs L. Evolution and functional classification of vertebrate gene deserts. Genome Res. 2005 Jan; 15(1):137-45. View in: PubMed

  53. Ahituv N, Rubin EM, Nobrega MA. Exploiting human--fish genome comparisons for deciphering gene regulation. Hum Mol Genet. 2004 Oct 01; 13 Spec No 2:R261-6. View in: PubMed

  54. Ovcharenko I, Nobrega MA, Loots GG, Stubbs L. ECR Browser: a tool for visualizing and accessing data from comparisons of multiple vertebrate genomes. Nucleic Acids Res. 2004 Jul 01; 32(Web Server issue):W280-6. View in: PubMed

  55. Boffelli D, Nobrega MA, Rubin EM. Comparative genomics at the vertebrate extremes. Nat Rev Genet. 2004 Jun; 5(6):456-65. View in: PubMed

  56. Nobrega MA, Fleming S, Roman RJ, Shiozawa M, Schlick N, Lazar J, Jacob HJ. Initial characterization of a rat model of diabetic nephropathy. Diabetes. 2004 Mar; 53(3):735-42. View in: PubMed

  57. Nobrega MA, Pennacchio LA. Comparative genomic analysis as a tool for biological discovery. J Physiol. 2004 Jan 01; 554(Pt 1):31-9. View in: PubMed

  58. Nobrega MA, Ovcharenko I, Afzal V, Rubin EM. Scanning human gene deserts for long-range enhancers. Science. 2003 Oct 17; 302(5644):413. View in: PubMed

  59. Yoon JW, Kita Y, Frank DJ, Majewski RR, Konicek BA, Nobrega MA, Jacob H, Walterhouse D, Iannaccone P. Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J Biol Chem. 2002 Feb 15; 277(7):5548-55. View in: PubMed

  60. Kwitek AE, Tonellato PJ, Chen D, Gullings-Handley J, Cheng YS, Twigger S, Scheetz TE, Casavant TL, Stoll M, Nobrega MA, Shiozawa M, Soares MB, Sheffield VC, Jacob HJ. Automated construction of high-density comparative maps between rat, human, and mouse. Genome Res. 2001 Nov; 11(11):1935-43. View in: PubMed

  61. Nobrega MA, Shiozawa M, Koike G, Jacob HJ, Miano JM. Gene structure and chromosomal mapping of the rat smooth muscle calponin gene. Mamm Genome. 2000 Feb; 11(2):115-9. View in: PubMed

  62. Berlani RE, Bonitz SG, Coruzzi G, Nobrega M, Tzagoloff A. Transfer RNA genes in the cap-oxil region of yeast mitochondrial DNA. Nucleic Acids Res. 1980 Nov 11; 8(21):5017-30. View in: PubMed