Tom Cooper Lab

Training

Master
Heading

Dr. Cooper's Associated Programs

Heading

Projects

Content

See the Projects page and contact Thomas Cooper, M.D. for updated information about specific projects.

Heading

Alternative Splicing Regulation:

Content
  • Determine the mechanisms for coordinated regulation during heart and skeletal muscle development using genome-wide approaches
  • Determine functional consequences of developmentally regulated protein isoform transitions resulting from alternative splicing
  • Identify the signaling events that modulate the activities of splicing regulators during development
Heading

Myotonic Dystrophy Pathogenesis:

Content
  • Identify the mechanism of muscle wasting in myotonic dystrophy using existing mouse models
  • Identify the mechanism of cardiomyopathy in myotonic dystrophy using existing mouse models
  • Identify the molecular mechanism of repeat-containing RNA toxicity
Heading

Lab Environment

Content

Our lab provides a scholarly, highly interactive, and productive scientific environment. The best ideas arise through consultation and discussion within and outside of the lab. Scientific investigations are most rewarding when they are goal-oriented, explore new areas, are directed toward understanding mechanisms, and have the potential for an important impact on human health. We believe that science is an exciting and rewarding career worthy of the invested time and energy.

Baylor College of Medicine provides a unique environment of outstanding research, collegiality and collaboration. From its excellent diversity of core facilities (including microarray, transgenic/KO mice, protein sequencing-mass spec), seven graduate programs, and large number of weekly seminar series to choose from, to its active postdoc association, Baylor is an active and well supported research community. Note that we are not associated with Baylor University (so we don't have a football team).

Our lab interacts regularly with at least ten other local labs focused on different aspects of RNA processing located at the MD Anderson Cancer Center, Rice University, Houston Methodist Research Institute and University of Texas Health Science Center at Houston. These labs gather two times per month for RNA Group Meeting, an informal joint lab meeting in which one lab presents recent results. This is a great opportunity to get outside input prior to submission of a grant or paper or for project development. These labs also participate in a regular monthly journal club. All of these institutions are located within walking distance of each other in the Texas Medical Center, the largest medical center in the world, a complex of more than 46 institutions including 13 academic institutions and populated by more than 90,000 people.

Heading

Training Goals

Content

Goals for trainees are to attain the abilities to independently: identify significant and practical scientific questions, design systematic strategies to address these questions, present ideas and findings in a variety of settings, from talking one-on-one to informal lab meetings and formal seminars, write up and submit results for publication, and prepare grant proposals. Trainees attend and present at national meetings. These should be the goals of people who are considering joining the lab. Rather than passively allowing trainees to sink or swim, Dr. Cooper believes that training for a scientific career is an active process involving ongoing interactions with and feedback from the PI and lab members.

Heading

Houston

Content

Houston is the fourth largest city in the United States with a population of 4 million. Activities abound (see links on the Life in Houston webpage) including opera, ballet, symphony, live theater, a large museum district (Houston is third in the country in the number of working visual artists), major-league sports (baseball, football, basketball), Galveston beaches (40 mile drive) and a huge number of restaurants offering a large variety of ethnic cuisine. A light rail system connects the medical center to downtown. Houston has all the amenities of a large city while being an affordable, friendly, and "easy" city in which to live. The bottom line is that, almost without exception, everyone who visits is impressed and surprised by what they didn't know (but thought they knew). Temperatures are cool and dry from fall to spring rarely dropping below freezing in the winter. Summer temperatures are in the 90's with moderate-high humidity but hey, it's air-conditioned everywhere.

Heading

First Author Publications

Content

First Author Publications from Cooper Lab Graduate Students and Postdocs Listed Alphabetically by Last Name of First Author

Bland, C.S. and Cooper, T.A. (2007) Micromanaging alternative splicing during muscle differentiation Dev Cell 12, 171-172

Bland, C.S., Wang, E.T., Vu, A., David, M.P., Castle, J.C., Johnson, J.M., Burge, C.B., and Cooper, T.A. (2010) Global regulation of alternative splicing during myogenic differentiation. Nucl. Acids Res. 38, 7651-7654

Brinegar, A.E., Zheng, X., Loehr J.A., Li, W., Rodney G.G., and Cooper T.A. (2017) Extensive alternative splicing transitions during postnatal skeletal muscle development are required for calcium handling functions. eLife 6:e27192.

Brinegar, A.E. and Cooper, T.A. (2016) Roles for RNA-binding proteins in development and disease. Brain Research .1647, 1-8.

Charlet-B., Savkur, R., Singh, G, N., Philips, A.V., Grice, E.A., and Cooper, T.A. (2002) Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol. Cell, 10, 45-53.

Charlet-B., Singh, G, N., Logan, P.E., and Cooper, T.A. (2002) Dynamic antagonism between CELF proteins and PTB regulate splicing of a muscle-specific exon in both muscle and nonmuscle cells. Mol. Cell 9, 649-658.

Cox, D.C. and Cooper, T.A. (2016) Non-canonical RAN Translation of CGG Repeats Has Canonical Requirements. Mol. Cell 62, 155-156.

Cox, D.C., Xiangnan, G., Xia, Z., and Cooper, T.A. (2020) Increased nuclear but not cytoplasmic activities of CELF1 protein leads to muscle wasting. Hum. Mol. Genet. 29, 1729-1744

Coulter, L., Landree, M., and Cooper, T.A. (1997) Identification of a new class of exonic splicing enhancers by in vivo selection. Mol. Cell. Biol. 17, 2143-2150.

Echeverria, G. V. and Cooper, T. A. (2012) RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity. Brain Research 1462, 100-111.

Echeverria, G.V. and Cooper, T.A. (2014) Muscleblind-like 1 activates insulin receptor exon 11 inclusion by enhancing U2AF65 binding and splicing of the upstream intron. Nucleic Acids Res. 42, 1893-1903.

Faustino, N.A. and Cooper, T.A. (2003) RNA splicing and human disease. Genes Dev. 17, 419-437.

Faustino, N.A. and Cooper, T.A. (2005) Identification of putative new splicing targets for ETR-3 using its SELEX sequences. Mol. Cell. Biol. 25, 879-887.

Gao, Z. and Cooper, T.A. (2012) Antisense oligonucleotides: rising stars in eliminating RNA toxicity in myotonic dystrophy. Human Gene Therapy 24, 499-507.

Gao, Z. and Cooper, T.A. (2013) Re-expression of PKM2 in type 1 myofibers correlates with altered glucose metabolism in myotonic dystrophy. Proc Natl Acad Sci U.S.A. 110, 13570-13575.

Giudice, J., Xia, Z., Li, W. & Cooper, T.A. Neonatal cardiac dysfunction and transcriptome changes caused by the absence of Celf1. Sci. Rep. 6, 35550 (2016).

Giudice J., Loehr J.A., Rodney G.G., and Cooper T.A. (2016) Alternative splicing of four trafficking genes regulates myofiber structure and skeletal muscle physiology. Cell Reports 17, 1923-1933.

Giudice, J. and Cooper, T. A. (2014) RNA binding proteins in heart development. Adv Exp Med Biol. 825, 389-429.

Giudice, J., Zheng, X., Wang, E.T., Scavuzzo, M.A., Ward, A.J., Kalsotra, A., Wei, W., Wehrens, X.H.T., Burge, C.B., Li, W. and Cooper, T.A. (2014) Alternative splicing regulates vesicular trafficking genes in cardiomyocytes during postnatal heart development. Nature Communications 5, 3603.

Goo, Y.H. and Cooper, T.A. (2009) CUGBP2 directly interacts with U2 17S snRNP components and promotes U2 snRNA binding to cardiac troponin T pre-mRNA. Nucl. Acids Res. 37, 4275-4286.

Grammatikakis, I. Goo, Y.H., Echeverria, G.V., and Cooper, T.A. (2011) Identification of MBNL1 and MBNL3 domains required for alternative splicing activation and repression. Nucl. Acids Res. 39, 2769-2780.

Han, J. and Cooper, T.A. (2005) Characterization of CELF splicing activation and repression domains in vivo Nucl. Acids Res. 33, 2769-2780.

Ho, T., Bundman, D., Armstrong, D.L., and Cooper, T.A. (2005) Transgenic mice expressing CUG-BP1 reproduce the myotonic dystrophy pattern of splicing. Hum. Mol. Genet. 14, 1539-1547.

Ho, T., Charlet-B., N., Poulos, M., Singh, G., Swanson, M.S., and Cooper, T.A. (2004) Muscleblind proteins regulate alternative splicing. EMBO J. 23, 3103-3112

Ho, T., Savkur, R.S., Poulos, M., Mancini., M.M., Swanson, M.S., and Cooper, T.A. (2005) Co-localization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophy J. Cell Science 118, 2923-2933.

Johnson, S. and Cooper, T.A. (2021) Overlapping mechanisms of lncRNA and expanded microsatellite RNA. Wiley Interdiscip Rev. RNA. 12, e1634. PMC7880542.

Kalsotra, A. , Tran, D., Ward, A., Xiao, X., Burge, C.B., Castle, J.M., Johnson, J.C., and Cooper, T.A. (2008) A conserved program of regulated alternative splicing during vertebrate heart development . Proc. Nat'l Acad. Sci. 105, 20333-20338.

Kalsotra, A. and Cooper, T. A. (2011) Functional consequences of developmentally regulated alternative splicing Nature Rev. Genet. 12, 715-729.

Kalsotra, A., Singh, R.K., Gurha, P., Ward, A.J., Creighton, C., and Cooper, T.A. (2014) The Mef2 transcription network is disrupted in myotonic dystrophy heart tissue dramatically altering miRNA and mRNA expression Cell Reports 6, 336-345.

Kalsotra, A., Wang, K, Li, P.-F., and Cooper, T. A. (2010) MicroRNAs coordinate an alternative splicing network during mouse postnatal heart development. Genes Dev. 24, 653-658.

Koshelev, M.V., Sarma, S., Wehrens, X.H.T., and Cooper, T.A. (2010) Heart-specific expression of CUGBP1 in transgenic mice reproduces electrocardiographic and functional abnormalities of DM1. Hum. Mol. Genet. 19, 1066-1075.

Kuyumcu-Martinez, N.M. and Cooper, T.A . (2006) Mis-regulation of alternative splicing causes pathogenesis in myotonic dystrophy. Prog. in Mol. Subcellular Biol. 44, 133-159.

Kuyumcu-Martinez, N.M., Wang, G.S., and Cooper, T.A. (2007) Increased steady state levels of CUG-BP1 in Myotonic Dystrophy 1 are due to PKC-mediated hyper-phosphorylation. Mol. Cell 28, 68-78.

Ladd, A.N. and Cooper, T.A. (2004) Nuclear-cytoplasmic localization of the RNA binding protein ETR-3 is controlled by multiple localization elements. J. Cell Science 117, 3519-3529.

Ladd, A.N. Stenberg, M.G., Swanson, M.S., and Cooper, T.A. (2005) A dynamic balance between activation and repression regulates pre-mRNA alternative splicing during heart development. Dev. Dyn. 233, 783-793.

Ladd, A.N., Charlet-B., N., and Cooper, T.A. (2001) The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing Mol. Cell. Biol. 21, 1285-1296.

Ladd, A.N., Cooper, T.A. (2002) Finding signals that regulate alternative splicing in the post-genomic era. Genome Biology 3, 8.1-8.16.

Ladd, A.N., Nguyen, N.H. Malhotra, K and Cooper, T.A. (2004) CELF6, a member of the CELF family of RNA binding proteins, regulates MSE-dependent alternative splicing. J. Biol. Chem. 279,17756-17764.

Ladd, A.N., Taffet, G.E., Hartley, C., Kearney , D.L. and Cooper, T.A. (2005) Cardiac-specific repression of CELF activity disrupts alternative splicing and causes cardiomyopathy. Mol. Cell. Biol. 25, 6267-6278.

Lee, J.E. and Cooper, T.A. (2009) Pathogenic Mechanisms of Myotonic Dystrophy. Biochem Soc Trans. 37, 1281-1286.

Lee, J.E., Bennett, C.F. and Cooper, T.A. (2012) RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1. Proc. Nat'l Acad. Sci. 109, 4221-4226.

Lucas, L. and Cooper, T.A. (2023 Insights into cell-specific functions of microtubules in skeletal muscle development and homeostasis. International Journal of Molecular Sciences (In Press).

Manning, K.S., Rao, A.N., Castro, M. and Cooper, T.A. (2017) BNANC gapmers revert splicing defects and reduce RNA foci with low toxicity in myotonic dystrophy cell models. ACS Chem Biol. 12, 2503-2509.

Manning, K.S. and Cooper, T.A. (2017) The roles of RNA processing in translating genotype to phenotype. Nature Reviews Mol. Cell. Biology 18, 102-114.

Morriss, G. R. and Cooper, T. A. Protein sequestration as a normal function of long noncoding RNAs and a pathogenic mechanism of RNAs containing nucleotide repeat expansions. Hum. Genet. (2017). doi:10.1007/s00439-017-1807-6

Morriss, G.R., Rajapakshe, K., Huang, S., Coarfa, C. and Cooper, T.A. (2018) Mechanisms of skeletal muscle wasting in a mouse model for myotonic dystrophy type 1. (In press, Hum. Mol. Genet.)

Nitschke, L. and Cooper, T.A. (2024) Combinatorial effects of ion channel mis-splicing as a cause of myopathy in myotonic dystrophy. J. Clin. Invest. 134, e176089.

Nitschke, L., Hu, R-C, Miller, A.N., Lucas, L. and Cooper, T.A. (2023) Alternative splicing mediates the compensatory upregulation of MBNL2 upon MBNL1 loss-of-function. Nucl. Acids Res. 10.1093/nar/gkac1219. Online ahead of print.

Orengo, J., Bundman, D., and Cooper, T.A. (2006) A bichromatic fluorescent reporter for cell-based screens of alternative splicing Nucl. Acids Res. 34, e148.

Orengo, J.P. and Cooper, T.A. (2007) Alternative splicing in disease in Alternative splicing in the post-genomic era, B.R. Graveley and B. Blencowe, ed. Landes publishing; pp. 212-223.

Orengo, J.P., Chambon, P., Metzger, D., Mosier, D.R., Snipes, G.J. and Cooper, T.A. (2008) Expanded CTG repeats within the DMPK 3¹ UTR causes severe skeletal muscle wasting in an inducible mouse model for myotonic dystrophy. Proc. Nat¹l Acad. Sci. 105, 2646-2651.

Orengo, J.P., Ward, A.J., and Cooper T.A. (2011) Alternative splicing misregulation secondary to skeletal muscle regeneration. Annals Neurology 69, 681-690.

Pang, P.D., Alsina, K.M., Cao, S., Koushik, A.B., Wehrens, X.H.T., Cooper, T.A. (2018) CRISPR-mediated expression of the fetal Scn5a isoform in adult mice causes conduction defects and arrhythmias. J. Amer. Heart Assoc. (In press).

Pedrotti, S., Giudice, J., Dagnino-Acosta, A., Knoblauch, M., Singh, R.K., Hanna, A., Mo, Q., Hicks, J., Hamilton, S.L., Cooper, T.A. (2015) The RNA-binding protein Rbfox1 regulates splicing required for skeletal muscle structure and function Human Molecular Genetics 24, 2360-2374.

Pedrotti, S. and Cooper, T.A. (2014) (Mis)-splicing in disease. Journal of Pathology. J. Pathology 233, 1-3.

Penna, M. S., Hu, R.-C., Rodney, G. G. & Cooper, T. A. (2023) The role of Limch1 alternative splicing in skeletal muscle function. Life Sci Alliance 6, e202201868.

Peterson, J. and Cooper, T.A. (2022) Clinical and molecular insights into gastrointestinal dysfunction in myotonic dystrophy types 1 & 2. International Journal of Molecular Sciences 23, 14779. PMC9737721.

Philips, A.V. and Cooper, T.A. (2000) RNA and human disease. Cell. Mol. Life Sci. 57, 235-249.

Philips, A.V., Timchenko, L.T., and Cooper, T.A. (1998) Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280, 737-741.

Rao, AN. and Cooper, T.A. (2017) A Therapeutic Double Whammy: Transcriptional or Post-transcriptional Suppression of Microsatellite Repeat Toxicity by Cas9. Mol. Cell 68:473–475.

Rao, A.N., Campbell, H.W., Guan, X, Word, T.A., Wehrens, X.H.T, Xia, Z. and Cooper, T.A. (2021) Reversible cardiac disease features in an inducible CUG-repeat RNA expressing mouse model of myotonic dystrophy. J. Clin. Invest. Insight. 8, 143465.

Ryan, K.J. and Cooper, T.A. (1996) Muscle-specific splicing enhancers regulate inclusion of the cardiac troponin T alternative exon in embryonic skeletal muscle. Mol. Cell. Biol. 16, 4014-4023.

Ryan, K.J., Charlet-B., N., and Cooper, T.A. (2000) Binding of PurH to a muscle-specific splicing enhancer correlates with exon inclusion in vivo. J. Biol. Chem. 275, 20618-20626.

Savkur, R., Philips, A.V., and Cooper, T.A. (2001) Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet. 29, 40-47.

Savkur, R.S., Philips, A.V., Cooper, T.A., Dalton, J.C., Moseley, M.L., Ranum, L.P.W., Day, J.W. (2004) Insulin receptor splicing alteration in myotonic dystrophy type 2. Am. J. Hum. Genet. 74:1309-1313.

Sharp, L., Cox, D.C. and Cooper, T.A. (2019) Endurance exercise leads to beneficial effects in a mouse model of myotonic dystrophy type 1. Muscle and Nerve 60, 779–789.

Sharpe, J. J. and Cooper, T. A. Unexpected consequences: exon skipping caused by CRISPR-generated mutations. Genome Biol. 18, 109 (2017).

Singh, R.K. and Cooper, T. A. (2012) Pre-mRNA splicing in disease and therapeutics. Trends in Molecular Medicine 18, 472-482.

Singh, R.K., Zheng, X., Bland, C.S., Kalsotra, A., Scavuzzo, M.A., Curk, T., Ule, J., Li, W. and Cooper, T. A. (2014) Rbfox2-coordinated alternative splicing of Mef2d and Rock2 controls myoblast fusion during myogenesis. Mol. Cell Mol Cell 55, 592-603.

Singh, R.K., Kolonin, A.M., Fiorotto, M.L. and Cooper, T. A. (2018) Rbfox splicing factors maintain skeletal muscle mass by regulating calpain3 and proteostasis. Cell Reports 24, 197-208.

Wang, G.S. and Cooper T.A. (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nature Rev. Genet. 8, 749-761.

Wang, G.S., Kearney, D.L., De Biasi, M., Taffet, G.E., and Cooper, T.A. (2007) Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy. J. Clin. Invest. 117, 2802-2811.

Wang, G.S., Kuyumcu-Martinez, N.M., Mathur, N., Wehrens, X.H., and Cooper, T.A. (2009) Protein kinase C inhibition ameliorates the cardiac phenotype of a mouse model for myotonic dystrophy, type 1. J. Clin. Invest. 119, 3797-3806. Lee, J.E. and Cooper, T.A. (2009) Pathogenic Mechanisms of Myotonic Dystrophy. Biochem Soc Trans. Biochem Soc Trans. 37, 1281-1286.

Ward, A. and Cooper, T.A. (2010) The pathobiology of alternative splicing. J. Path. 220, 152-163.

Ward, A.J., Rimer, M., Killian, J.M., Dowling, J.J., Cooper, T.A. (2010) CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1. Hum Mol Genet. 19, 3614-3622.