Michelle Hastings, Ph.D. Assistant Professor
Hastings Lab Website
Dr. Hastings earned an undergraduate degree in Biology from St. Olaf College in 1992 and went on to receive a Ph.D. in Biology from Marquette University in 1998. She was a postdoctoral fellow at Cold Spring Harbor Laboratory from 1998-2006 and a senior fellow until 2007. She joined the faculty at the Chicago Medical School as an Assistant Professor in the fall of 2007.
Pre-mRNA splicing is a critical step in eukaryotic gene expression. Defects in the splicing process cause many different human diseases and mutations that alter splicing are common. We are investigating mechanisms of pre-mRNA splicing and regulation of alternative splicing and applying these insights to determine how splicing is deregulated in disease.
Splicing is carried out by the spliceosome, a large macromolecular machine composed of >100 proteins. The majority of the proteins in the spliceosome have unknown or ambiguous functions in the splicing reaction but are likely important for helping the spliceosome carry out its primary functions: recognition of splice sites, efficient and accurate removal of introns and religation of exons. We use biochemical and cellular approaches to identify splicing factors based on their function in splicing and we characterize their role in splicing. Most recently we have identified the spliceosomal protein PUF60 as a critical component in 3’ splice site recognition. We are currently investigating the role of PUF60 in alternative splicing. We are also using similar approaches to identify additional splicing factors based on their unique functions.
Another focus of the lab is on understanding the molecular basis of the pediatric neurodegenerative disease spinal muscular atrophy (SMA). One promising approach for SMA therapy is to improve splicing and thereby expression, of a modifying gene, SMN2. We have identified a small-molecule that improves SMN2 splicing and we are currently optimizing the activity of these molecules for pre-clinical application. Small molecules that improve the splicing reaction have not been previously identified. We are investigating the mechanism by which these molecules alter splicing in order to learn about the splicing reaction and to identify potential novel targets for disease therapies.
One aspect of splicing that is intriguing is the recognition and removal of introns with non-canonical or unusual sequence characteristics. We are interested in the mechanisms of splicing of the minor, U12-dependent splicing pathway that excises a subset of introns with distinct splice sites. This pathway appears to have a mechanism for maintaining splicing fidelity that is distinct from the major splicing pathway. We have also recently characterized some unusual splice sites that are used as either 5’ and 3’ splice sites. Understanding these unusual splicing events will provide insights into the process of splicing as well as to the evolution of splice sites and mechanisms of splicing deregulation.
Jodelka, F.M., Ebert, A.D., Duelli, D.M., and Hastings, M.L. (2010) A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2. Hum. Mol. Genet.
Pigati, L., Yaddanapudi, S., Iyengar, R., Kim, D.J., Hearn, S., Danforth, D., Hastings M.L., Duelli, D.M. (2010) Selective Release of MicroRNA Species from Normal and Malignant Mammary Epithelial Cells. PLoS One. http://dx.plos.org/10.1371/journal.pone.0013515
Salato, V.K., Rediske, N.W., Zhang, C., Hastings, M.L., and Munroe, S. H. (2010) An exonic splicing enhancer within a bidirectional coding sequence regulates splicing of thyroid hormone receptor mRNA. RNA Biology, 7: 179-90.
Hastings, M.L., Berniac, J., Liu, Y.H., Abato, P., Jodelka, F.M., Barthel, L., Kumar, S., Dudley, C., Larson, K., Edmonds, J., Bowser, T., Draper, M., Higgins, P., and Krainer, A.R. (2009) Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy. Science Translational Medicine 1: 5ra12.
Araujo, M., Bonnal, S., Hastings, M.L., Krainer, A.R. and Valcarcel, J. (2009) Differential 3¹ splice site recognition of SMN1 and SMN2 transcripts by U2AF and U2 snRNP. RNA 15: 515-523.
Hastings, M.L. and Sachidanandam, R. (2008) Evolutionary conservation of splice sites. In: Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0020782.
Zhang, C., Hastings, M.L., Krainer, A.R. and Zhang, M.Q. (2007) Dual-specificity splice sites are used as both 5¹ and 3¹ splice sites. Proc. Natl. Acad. Sci. USA 104: 15028.
Hastings, M.L., Allemand, E., Duelli, D.M., Myers, M.P. and Krainer, A.R. (2007) Cooperation between PUF60 and U2AF65 determines pre-mRNA splicing efficiency and alternative splice-site choice. PLoS ONE 2: e538.
Allemand, E., Hastings, M.L., Murray, M.V., Myers, M.P. and Krainer, A.R. (2007) Alternative splicing regulation by interaction of phosphatase PP2Cg and nucleic acid-binding protein YB-1. Nature Struct. Mol. Biol. 14: 630-638.
Sheth, N., Roca, X., Hastings, M.L., Roeder, T., Krainer, A.R. and Sachidanandam, R. (2006) Comprehensive splice-site analysis using comparative genomics. Nucleic Acids Res.34: 3955-3967.
Cartegni, L.*, Hastings, M.L.*, Calarco, J.A., de Stanchina, E. and Krainer, A.R. (2006) Determinants of exon 7 identity in the spinal muscular atrophy genes, SMN1 and SMN2. Am. J. Hum. Genet. 78: 63-77. *equal contributors
Hastings, M.L., Resta, N., Traum, D., Stella, A., Guanti, G. and Krainer, A.R. (2005). An LKB1 AT-AC intron causes Peutz-Jeghers syndrome via splicing at non-canonical cryptic splice sites. Nature Struct. Mol. Biol. 12: 54-59
Hastings, M.L. and Krainer, A.R. (2001). Pre-mRNA splicing in the new millennium. Curr. Opin. Cell Biol. 13:302-309.
Hastings, M.L. and Krainer, A.R. (2001). Functions of SR proteins in the U12-dependent AT-AC pre-mRNA splicing pathway. RNA 7:471-482.
Hastings, M.L., Wilson, C.M. and Munroe, S.H. (2001). A purine-rich intronic element enhances alternative splicing of thyroid hormone receptor mRNA. RNA 7:859-874.
Hastings, M.L., Ingle, H.A., Lazar, M.A. and Munroe, S.H. (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.
Hastings, M.L., Milcarek, C., Martincic, K., Peterson, M.L. and Munroe, S.H. (1997). Expression of the thyroid hormone receptor gene, erbAa, in B lymphocytes: alternative mRNA processing is independent of differentiation but correlates with antisense RNA levels. Nucleic Acids Res. 25: 4296-4300.
Michelle Hastings, Ph.D. Department of Cell Biology and Anatomy The Chicago Medical School 3333 Green Bay Road North Chicago, Illinois 60064
Email: michelle.hastings@rosalindfranklin.edu Phone: (847) 578-8517 Fax: (847) 578-3253