Marcelo Nobrega, M.D. Ph.D.


Telephone number: 773 834 7919

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 andTBX5 – 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

Obesity-associated variants within FTO form long-range functional connections with IRX3. Smemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gomez-Marin C, Aneas I, Credidio FL, Sobreira DR, Wasserman NF, Lee JH, Puviindran V, Tam D, Shen M, Son JE, Vakili NA, Sung HK, Naranjo S, Acemel RD, Manzanares M, Nagy A, Cox NJ, Hui CC, Gomez-Skarmeta JL, Nobrega MA. (2014 Mar) Nature. 2014 Mar 20;507(7492):371-5. doi: 10.1038/nature13138. Epub 2014 Mar 12.24646999

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. (2014 Mar) J Clin Invest. 2014 Mar 18. pii: 73140. doi: 10.1172/JCI73140. 24642470

Beyond the ENCODE project: using genomics and epigenomics strategies to study enhancer evolution. Sakabe NJ, Nobrega MA. (2013 Dec) Philos Trans R Soc Lond B Biol Sci. 2013 Nov 11;368(1632):20130022. doi: 10.1098/rstb.2013.0022. Print 2013 Dec 19. 24218635 ( Full Text )

Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease. Smemo S, Campos LC, Moskowitz IP, Krieger JE, Pereira AC, Nobrega MA. (2012 Jul) Hum Mol Genet. 2012 Jul 15;21(14):3255-63. doi: 10.1093/hmg/dds165. Epub 2012 Apr 27.22543974 ( Full Text )

Dual transcriptional activator and repressor roles of TBX20 regulate adult cardiac structure and function. Sakabe NJ, Aneas I, Shen T, Shokri L, Park SY, Bulyk ML, Evans SM, Nobrega MA. (2012 May) Hum Mol Genet. 2012 May 15;21(10):2194-204. doi: 10.1093/hmg/dds034. Epub 2012 Feb 10. 22328084 ( Full Text )

Transcriptional enhancers in development and disease. Sakabe NJ, Savic D, Nobrega MA. (2012) Genome Biol. 2012 Jan 23;13(1):238. doi: 10.1186/gb-2012-13-1-238. 22269347 ( Full Text )

Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function. 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. (2011 Dec) J Clin Invest. 2011 Dec;121(12):4640-54. doi: 10.1172/JCI59472. Epub 2011 Nov 14.22080862 ( Full Text )

Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism. Savic D, Ye H, Aneas I, Park SY, Bell GI, Nobrega MA. (2011 Sep) Genome Res. 2011 Sep;21(9):1417-25. doi: 10.1101/gr.123745.111. Epub 2011 Jun 14.21673050 ( Full Text )

An 8q24 gene desert variant associated with prostate cancer risk confers differential in vivo activity to a MYC enhancer. Wasserman NF, Aneas I, Nobrega MA. (2010 Sep) Genome Res. 2010 Sep;20(9):1191-7. doi: 10.1101/gr.105361.110. Epub 2010 Jul 13.20627891 ( Full Text )

Genome-wide maps of transcription regulatory elements. Sakabe NJ, Nobrega MA. (2010 Jul) Wiley Interdiscip Rev Syst Biol Med. 2010 Jul-Aug;2(4):422-37. doi: 10.1002/wsbm.70.20836039

Homotypic clusters of transcription factor binding sites are a key component of human promoters and enhancers. Gotea V, Visel A, Westlund JM, Nobrega MA, Pennacchio LA, Ovcharenko I. (2010 May) Genome Res. 2010 May;20(5):565-77. doi: 10.1101/gr.104471.109. Epub 2010 Apr 2.20363979 ( Full Text )

Genome-wide discovery of human heart enhancers. Narlikar L, Sakabe NJ, Blanski AA, Arimura FE, Westlund JM, Nobrega MA, Ovcharenko I. (2010 Mar) Genome Res. 2010 Mar;20(3):381-92. doi: 10.1101/gr.098657.109. Epub 2010 Jan 14.20075146 ( Full Text )

A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development. Moskowitz IP, Kim JB, Moore ML, Wolf CM, Peterson MA, Shendure J, Nobrega MA, Yokota Y, Berul C, Izumo S, Seidman JG, Seidman CE. (2007 Jun) Cell. 2007 Jun 29;129(7):1365-76. 17604724

Predicting tissue-specific enhancers in the human genome. Pennacchio LA, Loots GG, Nobrega MA, Ovcharenko I. (2007 Feb) Genome Res. 2007 Feb;17(2):201-11. Epub 2007 Jan 8. 17210927 ( Full Text )

In vivo enhancer analysis of human conserved non-coding sequences. 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. (2006 Nov) Nature. 2006 Nov 23;444(7118):499-502. Epub 2006 Nov 5. 17086198

Identifying synonymous regulatory elements in vertebrate genomes. Ovcharenko I, Nobrega MA. (2005 Jul) Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W403-7. 15980499 ( Full Text )

In vivo characterization of a vertebrate ultraconserved enhancer. Poulin F, Nobrega MA, Plajzer-Frick I, Holt A, Afzal V, Rubin EM, Pennacchio LA. (2005 Jun) Genomics. 2005 Jun;85(6):774-81. Epub 2005 Apr 15. 15885503

Evolution and functional classification of vertebrate gene deserts. Ovcharenko I, Loots GG, Nobrega MA, Hardison RC, Miller W, Stubbs L. (2005 Jan) Genome Res. 2005 Jan;15(1):137-45. Epub 2004 Dec 8. 15590943 ( Full Text )

Megabase deletions of gene deserts result in viable mice. Nobrega MA, Zhu Y, Plajzer-Frick I, Afzal V, Rubin EM. (2004 Oct) Nature. 2004 Oct 21;431(7011):988-93. 15496924

Comparative genomics at the vertebrate extremes. Boffelli D, Nobrega MA, Rubin EM. (2004 Jun) Nat Rev Genet. 2004 Jun;5(6):456-65. 15153998

Scanning human gene deserts for long-range enhancers. Nobrega MA, Ovcharenko I, Afzal V, Rubin EM. (2003 Oct) Science. 2003 Oct 17;302(5644):413. 14563999