PORT B331/GOLD A325C
Ph.D., John Hopkins University, 1970
Current: Regulation of gene expression in aneuploidy. How is gene expression altered due to an extra chromosome 21 in Down Syndrome?
Past: Mechanisms of pre-mRNA processing: splicing and 3' end formation; logic of gene organization on C. elegans chromosomes: eukaryotic operons.
Current: I am now the Director of the Linda Crnic Institute for Down Syndrome, headquartered at the Anschutz Medical Campus (AMC), and with a significant component in Boulder. My laboratory is now at the AMC, where we are studying altered regulation as a consequence of trisomy 21. We are looking in cell lines derived from people with Down syndrome to determine the source of the high variability of symptoms associated with the syndrome. In addition, we are studying protein levels in blood, searching for biomarkers and possible therapeutic targets associated with particular issues faced by those with Down syndrome
Past: My laboratory worked on the small nematode worm, C. elegans, as a model to understand gene regulation and expression in higher animals. In the process of studying mechanisms of mRNA splicing in C. elegans, our laboratory discovered that a significant proportion of genes in this animal are arranged and transcribed in a manner quite similar to bacterial operons. This is very unusual in eukaryotes and previously unheard of in animals. The polycistronic pre-mRNAs are converted into monocistronic units by cleavage and polyadenylation and by trans-splicing. 1) What mechanisms are involved in processing of the polycistronic mRNAs? 2) Do the C. elegans operons serve the purpose of co-regulating genes whose products function together, as operons do in bacteria? and 3) How and when did operons arise during eukaryotic evolution? Like genes in other animals, C. elegans genes contain introns that are spliced out by spliceosomes. However, C. elegans has another type of splicing, mechanistically quite similar to removal of introns, called trans-splicing, in which a short leader is spliced onto the 5' ends of mRNAs. Recognition of a trans-splice site requires only that the pre-mRNA have a 3' splice site with no upstream 5' splice site. Although, C. elegans has two spliced leaders, SL1 and SL2, only SL1 is utilized in such situations. SL2 is reserved for genes located in downstream positions in operons. There is a close connection between formation of the 3' end of the upstream gene and trans-splicing about 100 nucleotides downstream at the 5' end of the next gene in the polycistronic pre-mRNA.
A global analysis of C. elegans trans-splicing
Allen, MA, Hillier, LW, Waterston, RH, and Blumenthal, T Genome Research, 21(2):255–264. 2011
Identification of transcription start sites of trans-spliced genes: uncovering unusual operon arrangements
Morton, JJ and Blumenthal, T RNA (New York, N.Y.), 17(2):327–337. 2011
Polycistronic pre-mRNA processing in vitro: snRNP and pre-mRNA role reversal in trans-splicing
Lasda, EL, Allen, MA, and Blumenthal, T Genes & Development, 24(15):1645–1658. 2010
RNA polymerase II C-terminal domain phosphorylation patterns in Caenorhabditis elegans operons, polycistronic gene clusters with only one promoter
Garrido-Lecca, A and Blumenthal, T Molecular and Cellular Biology, 30(15):3887–3893. 2010
RNA processing in C. elegans
Morton, JJ and Blumenthal, T Methods in Cell Biology, 106:187–217. 2011
Lasda, EL and Blumenthal, T Wiley Interdisciplinary Reviews. RNA, 2(3):417–434. 2011
The Transcription Start Site Landscape of C. elegans.
Saito, T.L., Hashimoto, S., Gu, S.G., Morton, J.J., Stadler, M., Blumenthal, T., Fire, A. and Morishita, S., Genome Research. 23(8):134‐1361.