Research Description

Our group is interested in dissecting the architecture and function of genes and their regulatory networks. We investigate how the multiple transcriptional enhancers, repressors, and boundary elements connected to a gene interact and orchestrate the precise tissue-specific and temporal-specific expression pattern of that gene. Understanding this process is critical since it is thought that malfunction of the regulatory program of key genes underlie the cause of several human diseases.

Our main focus in the lab is on the regulation of genes controlling heart development and congenital heart diseases. We focus both on dissecting the cis-regulatory landscape of key transcription factors in the heart – TBX20 and TBX5 – and also pursue genome-wide approaches such as ChIP-seq and RNA-seq to understand the regulatory architecture of the developing heart and localize heart enhancers. We employ other experimental tools such as mouse and zebrafish genetic engineering, transgenic reporter assay screens for regulatory potential, comparative genomics and bioinformatics analysis.

A second area of interest in the lab is testing the hypothesis that genome-wide association study (GWAS) hits in non-coding DNA are due to variation within long-range regulatory elements (enhancers or repressors) controlling the expression of nearby genes. Studies interrogating the regulatory landscape of three GWAS loci – intronic regions in TCF7L2 and FTO associated with type two diabetes and obesity, respectively, and a gene desert upstream of MYC associated with numerous cancers – are currently ongoing.

Selected Publications

• Sakabe NJ, Nobrega MA. Genome-wide maps of transcription regulatory elements. Wiley Interdiscip Rev Syst Biol Med. Jul-Aug;2(4):422-37, 2010.
• 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. Sep;20(9):1191-7, 2010.
• 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. May;20(5):565-77, 2010.
• Narlikar L, Sakabe NJ, Blanski AA, Arimura FE, Westlund JM, Nobrega MA, Ovcharenko I. Genome-wide discovery of human heart enhancers. Genome Res. Mar;20(3):381-92, 2010.
• 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. Jun 29;129(7):1365-76, 2007.
• Pennacchio LA, Loots GG, Nobrega MA, Ovcharenko I. Predicting Tissue-Specific Enhancers in the Human. Genome Research. Feb;17(2):201-11, 2007.
• 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 Noncoding Sequence. Nature 444(7118):499-502, 2006.
• Ovcharenko I, Nobrega MA. Identifying synonymous regulatory elements in vertebrate genomes. Nucleic Acids Res. 33: W403-7, 2005.
• Poulin F, Nobrega MA, Plajzer-Frick I, Holt A, Afzal V, Rubin EM, Pennacchio LA. In vivo characterization of a vertebrate ultraconserved enhancer. Genomics. 85(6):774-781, 2005.
• Boffelli D, Nobrega MA, Rubin EM. Comparative genomics at the vertebrate extremes. Nat Rev Genet.;5(6):456-65, 2004.
• Ovcharenko I, Loots GG, Nobrega MA, Hardison RC, Miller W, Stubbs L. Evolution and functional classification of vertebrate gene deserts. Genome Res. 15(1):137-45, 2005.
• Nobrega MA, Zhu Y, Plajzer-Frick I, Afzal V, Rubin EM. Megabase deletions of gene deserts result in viable mice. Nature. 21;431(7011):988-93, 2004.
• Nobrega MA, Ovcharenko I, Afzal V, Rubin EM. Scanning human gene deserts for long-range enhancers. Science. 302(5644):413, 2003