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Member, Institute of Molecular Biology
B.A., University of Colorado, Boulder, 1992.
Ph.D., Brandeis University, 1997 (Michael Rosbash). Postdoctoral: University
of Colorado, 1998-2000 (Steve Schultz), 2000-01 (Tom Cech). Honors and Awards:
Burroughs Wellcome Fund Fellow of the Life Sciences Research Foundation
1998-2001; Basil O’Connor Scholar 2004-06. At Oregon since 2002.
Research Interests:
The primary goal of the Berglund lab is to understand how introns are recognized in the process of pre-mRNA splicing. Pre-mRNA splicing is conserved from yeast to humans and a complex molecular machine, the spliceosome, is responsible for removing introns from pre-mRNAs. The factors shown in the figure (U1 snRNP - an RNA-protein particle, U2AF65, U2AF35 and BBP/SF1) are the primary factors responsible for initial intron recognition. We are using both biochemical and biophysical techniques to study these RNA-RNA, RNA-protein and protein-protein interactions. These interactions are critical because without the correct choice of splice sites, truncated proteins or proteins with the wrong sequence would be produced. Incorrect splice site selection is thought to be responsible for 15% or more of human diseases.
We are characterizing these RNA-RNA and RNA-protein interactions from multiple organisms. These include the yeast Saccharomyces cerevisiae which is an excellent model system because the introns are small and apparently there is very little or no regulation of splicing. However, in humans, the regulation of pre-mRNA splicing is very important. Almost all genes in humans contain introns and many of these genes are regulated at the level of pre-mRNA splicing. This regulation frequently results in alternative splicing which suggests that although there are only approximately 25,000 genes in the human genome the number of proteins produced is much higher than this. The control of this regulation occurs through RNA sequences found in either the intron or exon acting as either repressor or enhancer elements to influence the percentage of intron removal, splice-site selection, or exon skipping. The interplay of the factors that bind these enhancer/repressor elements and their interactions with the general splicing factors (U2AF65/35, BBP/SF1 and U1 snRNP, see figure) is another focus within the lab.
Myotonic Dystrophy
The splicing factor, muscleblind (MBNL), regulates alternative splicing
by affecting splice site selection (figure). Myotonic dystrophy (a form
of muscular dystrophy) occurs when MBNL does not properly function. The
dysfunction of MBNL occurs in a novel manner; in the disease state MBNL
is mis-localized and cannot act on its target pre-mRNAs. MBNL is mis-localized
by binding to CUG triplet expansion repeats in the 3’ UTR of the dystrophia
myotonia protein kinase (DMPK) gene. Hundreds of CUG repeats are common
in patients with myotonic dystrophy while unaffected individuals only have
five to 30 CUG repeats. Longer CUG repeats (1,000 or more) results in more
MBNL protein being mis-localized and leads to a more serious form of myotonic
dystrophy because the regulation of alternative splicing of various pre-mRNAs
is more severely compromised due to the increasing amounts of mis-localized
MBNL. Using biochemical and biophysical methods we are studying the interaction
between MBNL and the triplet expansion CUG repeats as well as MBNL’s
interactions with its normal pre-mRNA targets to gain insight into the molecular
mechanisms of myotonic dystrophy and alternative splicing.
Selected Publications:
Henscheid, K.L., Voelker, R., Berglund, J.A. 2007. Alternative modes of RNA binding by U2AF65 at the polypyrimidine tract. Biochemistry Web Release Date: 08-Dec-2007; (Article) DOI: 10.1021/bi701240t
Garrey, S.M., Cass, D.M., Wandler, A. M., Berglund, J.A. 2007. Transposition of two amino acids changes a promiscuous RNA binding protein into a sequence specific RNA binding protein. RNA Nov 13; [Epub ahead of print].
Warf, M.B., Berglund, J.A. 2007. MBNL binds similar RNA structures in the CUG repeats of myotonic dystrophy and its intronic pre-mRNA target in cardiac troponin T. RNA Dec;13(12):2238-51.
Voelker, R., Berglund, J.A. 2007. A Comprehensive Computational Characterization of Conserved Mammalian Intronic Sequences Reveals Conserved Motifs Associated with Constitutive and Alternative Splicing. Genome Research Jul;17(7):1023-33.
Garrey S. M., Voelker R., Berglund, J.A. 2006. An extended RNA binding site for the yeast branchpoint binding protein and the role of its Zn knuckle domains in RNA binding. J Biol Chem. 281(37): 27443-53.
Mooers, B.H.M., Logue, J.S., Berglund, J.A. 2005. The structural basis of myotonic dystrophy from the crystal structure of CUG repeats. Proc Natl Acad Sci U S A. 102(46):16626-31.
To Contact Dr. Berglund:
Phone: 541-346-5097
aberglund@molbio.uoregon.edu
WEBMASTER
lynde@uoregon.edu
