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Marcelo A. Nobrega

Professor
nobrega@uchicago.edu
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. African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans. Genome Med. 2022 09 29; 14(1):112. View in: PubMed

  2. Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer's disease among women. Alzheimers Dement. 2022 Jun 30. View in: PubMed

  3. Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries. Circ Res. 2022 01 21; 130(2):166-180. View in: PubMed

  4. Establishment of human induced trophoblast stem-like cells from term villous cytotrophoblasts. Stem Cell Res. 2021 10; 56:102507. View in: PubMed

  5. Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of IRX3 and IRX5. Science. 2021 06 04; 372(6546):1085-1091. View in: PubMed

  6. Pluripotent stem cell-derived endometrial stromal fibroblasts in a cyclic, hormone-responsive, coculture model of human decidua. Cell Rep. 2021 05 18; 35(7):109138. View in: PubMed

  7. Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression. Circulation. 2021 03 30; 143(13):1302-1316. View in: PubMed

  8. Altered transcriptional and chromatin responses to rhinovirus in bronchial epithelial cells from adults with asthma. Commun Biol. 2020 11 13; 3(1):678. View in: PubMed

  9. Altered Enhancer and Promoter Usage Leads to Differential Gene Expression in the Normal and Failed Human Heart. Circ Heart Fail. 2020 10; 13(10):e006926. View in: PubMed

  10. Advancing human health in the decade ahead: pregnancy as a key window for discovery: A Burroughs Wellcome Fund Pregnancy Think Tank. Am J Obstet Gynecol. 2020 09; 223(3):312-321. View in: PubMed

  11. Transcriptional Patterning of the Ventricular Cardiac Conduction System. Circ Res. 2020 07 17; 127(3):e94-e106. View in: PubMed

  12. Identification of atrial fibrillation associated genes and functional non-coding variants. Nat Commun. 2019 10 18; 10(1):4755. View in: PubMed

  13. Gene therapy for pathologic gene expression. Science. 2019 01 18; 363(6424):231-232. View in: PubMed

  14. 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

  15. A promoter interaction map for cardiovascular disease genetics. Elife. 2018 07 10; 7. View in: PubMed

  16. 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

  17. Reducing mitochondrial reads in ATAC-seq using CRISPR/Cas9. Sci Rep. 2017 05 26; 7(1):2451. View in: PubMed

  18. DNA methylation in lung cells is associated with asthma endotypes and genetic risk. JCI Insight. 2016 12 08; 1(20):e90151. View in: PubMed

  19. Editorial. Semin Cell Dev Biol. 2016 09; 57:1. View in: PubMed

  20. Probing chromatin landscape reveals roles of endocardial TBX20 in septation. J Clin Invest. 2016 08 01; 126(8):3023-35. View in: PubMed

  21. 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

  22. HIF1a Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes. Dev Cell. 2015 Jun 08; 33(5):507-21. View in: PubMed

  23. 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

  24. Targeted Germline Modifications in Rats Using CRISPR/Cas9 and Spermatogonial Stem Cells. Cell Rep. 2015 Mar 24; 10(11):1828-35. View in: PubMed

  25. 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

  26. 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

  27. 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

  28. TCF7L2 is a master regulator of insulin production and processing. Hum Mol Genet. 2014 Dec 15; 23(24):6419-31. View in: PubMed

  29. A common genetic variant within SCN10A modulates cardiac SCN5A expression. J Clin Invest. 2014 Apr; 124(4):1844-52. View in: PubMed

  30. 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

  31. 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

  32. Regulation of MEIS1 by distal enhancer elements in acute leukemia. Leukemia. 2014 Jan; 28(1):138-46. View in: PubMed

  33. FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA. Nat Commun. 2013; 4:1798. View in: PubMed

  34. Enhancers: five essential questions. Nat Rev Genet. 2013 04; 14(4):288-95. View in: PubMed

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

  36. In vitro scan for enhancers at the TCF7L2 locus. Diabetologia. 2013 Jan; 56(1):121-5. View in: PubMed

  37. TBX5 drives Scn5a expression to regulate cardiac conduction system function. J Clin Invest. 2012 Jul; 122(7):2509-18. View in: PubMed

  38. 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

  39. Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal. J Clin Invest. 2012 Jun; 122(6):2306-15. View in: PubMed

  40. 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

  41. A fine-scale chimpanzee genetic map from population sequencing. Science. 2012 Apr 13; 336(6078):193-8. View in: PubMed

  42. 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

  43. Transcriptional enhancers in development and disease. Genome Biol. 2012 Jan 23; 13(1):238. View in: PubMed

  44. Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function. J Clin Invest. 2011 Dec; 121(12):4640-54. View in: PubMed

  45. Modulation ofTcf7l2 expression alters behavior in mice. PLoS One. 2011; 6(10):e26897. View in: PubMed

  46. 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

  47. 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

  48. Genome-wide identification of conserved regulatory function in diverged sequences. Genome Res. 2011 Jul; 21(7):1139-49. View in: PubMed

  49. 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

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

  51. 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

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

  53. 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

  54. 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

  55. Genome-wide discovery of human heart enhancers. Genome Res. 2010 Mar; 20(3):381-92. View in: PubMed

  56. 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

  57. 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

  58. 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

  59. Predicting tissue-specific enhancers in the human genome. Genome Res. 2007 Feb; 17(2):201-11. View in: PubMed

  60. In vivo enhancer analysis of human conserved non-coding sequences. Nature. 2006 Nov 23; 444(7118):499-502. View in: PubMed

  61. Identifying synonymous regulatory elements in vertebrate genomes. Nucleic Acids Res. 2005 Jul 01; 33(Web Server issue):W403-7. View in: PubMed

  62. In vivo characterization of a vertebrate ultraconserved enhancer. Genomics. 2005 Jun; 85(6):774-81. View in: PubMed

  63. Evolution and functional classification of vertebrate gene deserts. Genome Res. 2005 Jan; 15(1):137-45. View in: PubMed

  64. Exploiting human--fish genome comparisons for deciphering gene regulation. Hum Mol Genet. 2004 Oct 01; 13 Spec No 2:R261-6. View in: PubMed

  65. 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

  66. Comparative genomics at the vertebrate extremes. Nat Rev Genet. 2004 Jun; 5(6):456-65. View in: PubMed

  67. Initial characterization of a rat model of diabetic nephropathy. Diabetes. 2004 Mar; 53(3):735-42. View in: PubMed

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

  69. Scanning human gene deserts for long-range enhancers. Science. 2003 Oct 17; 302(5644):413. View in: PubMed

  70. 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

  71. Automated construction of high-density comparative maps between rat, human, and mouse. Genome Res. 2001 Nov; 11(11):1935-43. View in: PubMed

  72. Gene structure and chromosomal mapping of the rat smooth muscle calponin gene. Mamm Genome. 2000 Feb; 11(2):115-9. View in: PubMed

  73. 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
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