B.A. 1968, Haverford College, Haverford, PA
Ph.D. 1974, Indiana University, Bloomington, IN
Postdoctoral Fellow, Harvard Medical School, Boston, MA
Postdoctoral Fellow, Worcester Foundation for Experimental Biology, Shrewsbury, MA
Recent analysis of the human genome suggests the presence of about 22,000 protein coding genes, far fewer than originally expected. However, other observations indicate a much greater level of genetic complexity than this number suggests. For example, most pre-mRNAs are alternatively spliced with some genes giving rise to dozens and even hundreds of mRNAs and proteins. In addition, most of the genome does 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 of unknown function. 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 α-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 developmental and 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 relevant context. We have identified three splicing enhancers that promote splicing of TRα2 mRNA, including one, designated ESX10, located within the bidirectional coding region for both TRα2 and Rev-erbα.
Other research, in collaboration with investigators at Marquette University and the National Institutes of Health, concerns the role of antisense RNA and mRNA-like non-coding RNA in the regulation of mammalian gene expression. This work is directed at identifying and characterizing non-coding RNAs with a focus on their role in mammalian gene regulation. Recent studies have described many thousands of pairs of overlapping genes in the mammalian genomes. A leading hypothesis is that many such overlaps act to regulate expression of proximal or overlapping mRNAs. The complexity of antisense and non-coding transcription poses many challenges that are fundamental for understanding the regulation of genes and their involvement in human genetic diseases.
Rindfleisch, B.C., Brown, M.S, VandeBerg, J.L., and Munroe,S.H. 2010. Structure and expression of two nuclear receptor genes in marsupials: insights into the evolution of the antisense overlap between the α-thyroid hormone receptor and Rev-erbα, BMC Molecular Biology, 11, 97 (14 pp).
Salato, V.K., Rediske, N.R., Zhang, C., Hastings, M.L., and Munroe, S.H. 2010. An exonic splicing enhancer within a bidirectional coding region regulates alternative splicing of an antisense mRNA. RNA Biology 7:179-190.
Munroe, S.H. and Zhu, J. 2006. Overlapping transcripts, double-stranded RNA and antisense regulation: A genomic perspective. Cell. Mol. Life Sci. 63, 2102-18.
Munroe, S.H., C. Zhang, C.M. Nemec and T.L. Hoff. 2011. Evolution and alternative processing of mRNA encoding the variant thyroid hormone receptor, TRα2, antisense to Rev-erbα. Sixteenth Annual Meeting of the RNA Society (Kyoto, Japan, June 14-18, 2011).
Munroe, S.H., C.M. Nemec, T.L. Hoff, M.S. Brown, B.C. Rindfleisch and C. Zhang. 2010. Functional analysis of conserved cis-acting elements within the antisense overlap between two nuclear receptor genes, TRα and Rev-erbα. Fifteenth Annual Meeting of the RNA Society (Seattle, Washington, June 22-27, 2010).
NIH Senior National Research Service Award (1987-88)