Marcelo A. Nobrega, MD 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.

Establishment of human induced trophoblast stem-like cells from term villous cytotrophoblasts.
Bai T, Peng CY, Aneas I, Sakabe N, Requena DF, Billstrand C, Nobrega M, Ober C, Parast M, Kessler JA. Establishment of human induced trophoblast stem-like cells from term villous cytotrophoblasts. Stem Cell Res. 2021 Aug 19; 56:102507.
PMID: 34454392

Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of IRX3 and IRX5.
Sobreira DR, Joslin AC, Zhang Q, Williamson I, Hansen GT, Farris KM, Sakabe NJ, Sinnott-Armstrong N, Bozek G, Jensen-Cody SO, Flippo KH, Ober C, Bickmore WA, Potthoff M, Chen M, Claussnitzer M, Aneas I, Nóbrega MA. Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of IRX3 and IRX5. Science. 2021 06 04; 372(6546):1085-1091.
PMID: 34083488

Pluripotent stem cell-derived endometrial stromal fibroblasts in a cyclic, hormone-responsive, coculture model of human decidua.
Cheung VC, Peng CY, Marinic M, Sakabe NJ, Aneas I, Lynch VJ, Ober C, Nobrega MA, Kessler JA. Pluripotent stem cell-derived endometrial stromal fibroblasts in a cyclic, hormone-responsive, coculture model of human decidua. Cell Rep. 2021 May 18; 35(7):109138.
PMID: 34010658

Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression.
Gacita AM, Fullenkamp DE, Ohiri J, Pottinger T, Puckelwartz MJ, Nobrega MA, McNally EM. Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression. Circulation. 2021 Mar 30; 143(13):1302-1316.
PMID: 33478249

Altered transcriptional and chromatin responses to rhinovirus in bronchial epithelial cells from adults with asthma.
Helling BA, Sobreira DR, Hansen GT, Sakabe NJ, Luo K, Billstrand C, Laxman B, Nicolae RI, Nicolae DL, Bochkov YA, Gern JE, Nobrega MA, White SR, Ober C. Altered transcriptional and chromatin responses to rhinovirus in bronchial epithelial cells from adults with asthma. Commun Biol. 2020 11 13; 3(1):678.
PMID: 33188283

Altered Enhancer and Promoter Usage Leads to Differential Gene Expression in the Normal and Failed Human Heart.
Gacita AM, Dellefave-Castillo L, Page PGT, Barefield DY, Wasserstrom JA, Puckelwartz MJ, Nobrega MA, McNally EM. 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.
PMID: 32993371

Advancing human health in the decade ahead: pregnancy as a key window for discovery: A Burroughs Wellcome Fund Pregnancy Think Tank.
Sadovsky Y, Mesiano S, Burton GJ, Lampl M, Murray JC, Freathy RM, Mahadevan-Jansen A, Moffett A, Price ND, Wise PH, Wildman DE, Snyderman R, Paneth N, Capra JA, Nobrega MA, Barak Y, Muglia LJ. 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.
PMID: 32565236

Transcriptional Patterning of the Ventricular Cardiac Conduction System.
Burnicka-Turek O, Broman MT, Steimle JD, Boukens BJ, Petrenko NB, Ikegami K, Nadadur RD, Qiao Y, Arnolds DE, Yang XH, Patel VV, Nobrega MA, Efimov IR, Moskowitz IP. Transcriptional Patterning of the Ventricular Cardiac Conduction System. Circ Res. 2020 07 17; 127(3):e94-e106.
PMID: 32290757

Identification of atrial fibrillation associated genes and functional non-coding variants.
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 10 18; 10(1):4755.
PMID: 31628324

TCF7L2 (Transcription Factor 7-Like 2) Regulation of GATA6 (GATA-Binding Protein 6)-Dependent and -Independent Vascular Smooth Muscle Cell Plasticity and Intimal Hyperplasia.
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.
PMID: 30567484

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