STEPHEN H. MUNROE
Professor

B.A. 1968, Haverford College
Ph.D. 1974, Indiana University
Postdoctoral Fellow, Harvard Medical School and Worcester Foundation for Experimental Biology

WLS 408
(414) 288-1485
email: stephen.munroe@marquette.edu

mRNA SPLICING AND ANTISENSE REGULATION

Recent analysis of the human genome suggests the presence of about 20,000 protein coding genes, far fewer than originally expected.  However, other observations indicate a much greater level of genetic complexity than this number suggests. Greater than 60% of pre-mRNAs transcripts are alternatively spliced with some genes giving rise to dozens and even hundreds of mRNAs and proteins.  In addition, most of the genome not code for protein or pre-mRNA at all.  Rather it is transcribed to yield non-coding RNAs, many of which are highly regulated, but their function is unknown,  non-coding RNAs.   My laboratory uses biochemical and genomic approaches to study the post-transcriptional regulation of mRNAs and non-coding RNAs in mammalian cells.   Our interests include the role of protein-RNA interactions in alternative splicing and the mechanisms of antisense regulation and other RNA-directed regulatory process.  This research involves two distinct areas of investigation.

For some years we have been studying alternative splicing and polyadenylation of mRNAs encoding two functionally antagonistic nuclear receptor proteins, TRα1 and TRα2.  TRα1 is the alpha-type thyroid hormone (T3) receptor which activates many types of genes in the presence of the hormone. TRα2 is a non-hormone binding variant that is highly expressed in most tissues in human and rat and appears to antagonize the response of canonical T3 receptors. An unusual feature of the TRα gene is that it overlaps another gene, Rev-erbα, on the opposite DNA strand.  Interestingly, Rev-erbα encodes a third nuclear receptor protein and like TRα plays diverse roles in metabolic regulation.  Several lines of evidence suggest that increased expression of the complementary Rev-erbα mRNA increases the ratio of TRα1 to TRα2 mRNAs, but this has yet to be demonstrated in a physiologically meaningful context.  We have recently identified three splicing enhancers that promote splicing of TRα2 mRNA, including one located within the bidirectional coding region for both TRα2 and Rev-erbα. 

Other research concerns the role of antisense RNA and mRNA-like non-coding RNA in the regulation of mammalian gene expression.  This work involves collaborations with a number of other investigators at Marquette University, Duke University and elsewhere. This work is directed at identifying and characterizing novel non-coding RNAs, with a focus on their role in regulating mammalian genes.   Recent studies demonstrate that there are thousands of pairs of overlapping genes within the mammalian genome.  A leading hypothesis is that many such overlaps involving non-coding RNAs act to regulate expression of overlapping or near-by mRNAs.  The complexity of antisense and non-coding transcription poses challenging questions for understanding fundamental questions concerning how genes are regulated in humans  

Selected Publications:

Hastings, M.L., H.A. Ingle, M.A. Lazar and S.H. Munroe. 2000. Post-transcriptional regulation of thyroid hormone receptor expression by cis-acting sequences and a naturally occurring antisense RNA. J. Biol. Chem. 275, 11507-11513.

Eperon, I.C., O. Makarova, A. Mayeda, S.H. Munroe, J. Cáceres, D.G. Hayward, and A.R. Krainer. 2000. Selection of alternative 5' splice sites: the role of U1 snRNP and models for the antagonistic effects of SF2/ASF and hnRNP A1. Mol. Cell. Biol. 20, 8303-8318.

Hastings, M.L., C.M. Wilson and S.H. Munroe. 2001. A purine-rich intronic element enhances alternative splicing of thyroid hormone receptor mRNA. RNA 7, 859-874.

Munroe, S.H. 2004. Diversity of antisense regulation in eukaryotes: multiple mechanisms, emerging patterns. J. Cell. Biochem. 93, 664-671.

Munroe, S.H. and J. Zhu 2006.  Overlapping transcripts, double-stranded RNA and antisense regulation: A genomic perspective.  Cell. Mol. Life Sci., 63:2102-18.

Graduate Assistant:

• Chao Zhang

Meeting presentations

Bestul, A., X. Wang, J.T. Anderson, and S. H. Munroe (2007) Biochemical and genetic analysis of a mouse DEAD-box protein homologous to yeast Mtr4p. National meeting of the American Society for Biochemistry and Molecular Biology  (Washington, DC, April 28-May 2).

Munroe, S.H., A. K. Schnell, E. Mackiel and C. Zhang (2008)  Terminal exon definition regulates alternative splicing of thyroid hormone receptor mRNA. 13th Annual Meeting of the RNA Society (Berlin, Germany July 27-Aug. 3).