Andy Berglund, Ph.D.
Center for NeuroGenetics
Professor – Biochemistry and Molecular Biology
Phone: (352) 273-7888
Fax: (352) 273-8284
University of Florida
Dept. of Biochemistry and Molecular Biology
2033 Mowry Rd.
Gainesville, FL. 32610
Dr. Berglund began studying biochemistry in 1990 with a focus on the structures that RNA can adopt and their role in biology. His interests expanded to determining the mechanisms through which RNA binding proteins recognize RNA motifs in pre-mRNA splicing. As a graduate student he was the first to show that proteins conserved from yeast to humans specifically recognize a RNA motif that is essential for the recognition and removal of introns in pre-mRNA splicing. In his own laboratory, he and his group began studying the molecular mechanisms of myotonic dystrophy. This lead to his laboratory solving the first crystal structure of CUG repeats. They have solved additional structures of CUG repeats leading to a better understanding of the dynamics of the repeats and insights into the toxicity of the repeats. One of the mechanisms through which the CUG repeats and CCUG repeats for myotonic dystrophy type 2 (DM2) are toxic is the sequestration of the muscleblind-like (MBNL) family of RNA binding proteins. The sequestration of MBNL proteins leads to many changes in splicing, which are implicated in causing the symptoms in DM. His laboratory, along with several other groups in the field, have identified some of the mechanisms through which the MBNL family of proteins regulate splicing providing a better framework for understanding the mis-splicing in myotonic dystrophy. For many years the group has investigated using small molecules to target the toxic CUG and CCUG repeats of DM. These efforts have lead to the identification of molecules that rescue the mis-splicing in DM1 cell and mouse models. Recently the group has shown that targeting the production of the toxic RNA shows promise as a potential approach to identify lead compounds for developing therapeutics.
Research in the Berglund lab
The Berglund lab continues to focus on myotonic dystrophy with the goal of translating basic science into clinical research using a combination of biochemical, cellular and genomic approaches. The lab is beginning to expand their research efforts into other neuromuscular diseases caused by microsatellite expansions to determine similarities and differences in the mechanisms across these diseases. These studies are important to build the necessary foundation of basic understanding that can be used to develop therapeutic strategies for DM, ataxia and ALS. A few of our current projects are briefly described. The characterization of many mis-splicing events from DM1 patients is leading to predictions on which splicing events are the best biomarkers for therapeutic studies. We plan to expand this approach to DM2. We are developing novel synthetic MBNL1 proteins that have altered activities providing insight into how this protein recognizes RNA and regulates splicing. A synthetic MBNL1 with improved activity could potentially be used in a therapeutic approach. We are developing approaches to screen libraries of small molecules and mining the scientific literature to identify compounds that can be used to inhibit the production of toxic RNAs. Lead compounds that show promise inhibiting the production of the toxic RNAs will be studied to understand the mechanisms through which they function to inform the development of molecules with improved activity. The goal of our research is to use the results from these fundamental studies to identify innovative strategies to reduce or correct the improper pre-mRNA splicing that occurs in the disease state. For example, we have recently shown that small molecules can be used to rescue the mis-splicing in cell and mouse models of myotonic dystrophy.
Wagner SD, Struck AJ, Gupta R, Farnsworth DR, Mahady AE, Eichinger K, Thornton CA, Wang ET, Berglund JA. Dose-Dependent Regulation of Alternative Splicing by MBNL Proteins Reveals Biomarkers for Myotonic Dystrophy. PLoS Genet. 2016 Sep 28;12(9):e1006316. doi: 10.1371/journal.pgen.1006316. PMCID: PMC5082313
Oddo JC, Saxena T, McConnell OL, Berglund JA, Wang ET. Conservation of context-dependent splicing activity in distant Muscleblind homologs. Nucleic Acids Res. 2016 Sep 30;44(17):8352-62. doi:10.1093/nar/gkw735. PMCID: PMC5041496
Siboni RB, Nakamori M, Wagner SD, Struck AJ, Coonrod LA, Harriott SA, Cass DM, Tanner MK, Berglund JA. Actinomycin D Specifically Reduces Expanded CUG Repeat RNA in Myotonic Dystrophy Models. Cell Rep. 2015 Dec 22;13(11):2386-94. doi: 10.1016/j.celrep.2015.11.028. Epub 2015 Dec 10. PMCID: PMC4691565
Siboni RB, Bodner MJ, Khalifa MM, Docter AG, Choi JY, Nakamori M, Haley MM, Berglund JA. Biological Efficacy and Toxicity of Diamidines in Myotonic Dystrophy Type 1 Models. J Med Chem. 2015 Aug 13;58(15):5770-80. doi: 10.1021/acs.jmedchem.5b00356. Epub 2015 Jul 21.
deLorimier E, Coonrod LA, Copperman J, Taber A, Reister EE, Sharma K, Todd PK, Guenza MG, Berglund JA. Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model. (2014) Nucleic Acids Res. Nov 10;42(20):12768-78. doi: 10.1093/nar/gku941. Epub 2014 Oct 10.
Wagner SD, Berglund JA. (2014) Alternative pre-mRNA splicing. Methods Mol Biol.;1126:45-54. doi: 10.1007/978-1-62703-980-24.
Coonrod LA, Nakamori M, Wang W, Carrell S, Hilton CL, Bodner MJ, Siboni RB, Docter AG, Haley MM, Thornton CA, Berglund JA. (2013) Reducing Levels of Toxic RNA with Small Molecules. ACS Chem Biol. Nov 15;8(11):2528-37. doi: 10.1021/cb400431f. Epub 2013 Sep 27.
Coonrod LA, Lohman JR, Berglund JA. (2012) Utilizing the GAAA tetraloop/receptor to facilitate crystal packing and structure determination of a CUG RNA helix. Biochemistry Oct 23;51(42):8330-7. doi: 10.1021/bi300829w. Epub 2012 Oct 12
Purcell J, Oddo JC, Wang ET, Berglund JA. (2012) Combinatorial Mutagenesis of MBNL1 Zinc Fingers Elucidates Distinct Classes of Splicing Regulatory Events. Mol Cell Biol. Oct;32(20):4155-67. Epub 2012 Aug 13.