Marcelo A. Nobrega, PhD

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.

A novel mechanism of inherited TBG deficiency: mutation in a liver-specific enhancer.
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.
PMID: 25361180

Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal.
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.
PMID: 22585572

DNA methylation in lung cells is associated with asthma endotypes and genetic risk.
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.
PMID: 27942592

Evidence of non-pancreatic beta cell-dependent roles of Tcf7l2 in the regulation of glucose metabolism in mice.
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.
PMID: 25398947

TBX5 drives Scn5a expression to regulate cardiac conduction system function.
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.
PMID: 22728936

Appendage expression driven by the Hoxd Global Control Region is an ancient gnathostome feature.
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.
PMID: 21765002

A common genetic variant within SCN10A modulates cardiac SCN5A expression.
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.
PMID: 24642470

The emerging genetic landscape underlying cardiac conduction system function.
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.
PMID: 21538814

Regulation of MEIS1 by distal enhancer elements in acute leukemia.
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.
PMID: 24022755

A promoter interaction map for cardiovascular disease genetics.
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.
PMID: 29988018

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