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 20,000-25,000 protein coding genes, far fewer than originally expected.  However, other observations indicate a much greater level of genetic complexity than these numbers suggest. At least 60% of transcripts from protein-coding genes are alternatively spliced and give rise to multiple mRNAs and proteins.  Many other genes produce non-coding RNAs that are expressed in a highly regulated manner.  Although the function of most non-coding RNAs is unknown non-coding RNAs may be as abundant as mRNAs.  My laboratory uses biochemical and genomic approaches to analyze  post-transcriptional regulation of gene expression in mammals.   Specific interests include the role of protein-RNA interactions in alternative splicing, mechanisms of antisense regulation and other RNA-directed regulatory process.  This research involves two distinct areas of investigation.

For some years now, we have been studying alternative splicing and polyadenylation of mRNAs encoding two functionally antagonistic nuclear receptor proteins, TRa1 and TRa2.  TRa1 is the alpha-thyroid hormone receptor and activates specific genes in the presence of the hormone. TRa2 is a non-hormone binding variant that antagonizes TRa1 function.  An unusual feature of the TRa gene is that it overlaps a gene on the opposite DNA strand that encodes a third nuclear receptor protein designated Rev-erba.  Several lines of evidence indicate that increased expression of the complementary Rev-erba mRNA increases the ratio of TRa1 to TRa2 mRNAs.  We have recently identified several splicing enhancers that promote splicing of TRa2 mRNA, including one that is located within the overlap region between TRa2 and Rev-erba.  Further experiments are aimed at understanding the possible physiological role of the complementary overlap between these two mRNAs.

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 several investigators at Marquette University, Duke University, Harvard University and elsewhere, is designed to explore broad questions concerning the role of role of novel RNA molecules in regulating gene expression within the mammalian genome.  Recent high throughput studies demonstrate that there are thousands of pairs of overlapping genes within the mammalian genome.  Many pairs include non-coding RNAs that may act as regulators of overlapping mRNAs.  The complexity of  antisense and non-coding transcription poses challenging questions for understanding genetic regulation in complex organisms.  As a first step towards investigating these questions, are using a custom-designed, high-density microarrays to examine the expression of a large number of RNAs in normal and genetically altered mouse cell lines.

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:

• Jack Littrell (Bioinformatics Program)

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 and E Mackiel (2007) Role of polyadenylation in the alternative processing of mRNAs for thyroid hormone receptor.  12^th Annual Meeting of the RNA Society (Madison, WI, May 29-June 3).