Alan M. Zahler

Professor of Molecular, Cell and Developmental Biology
B.S., Carnegie-Mellon University
Ph.D., University of Colorado, Boulder
Postdoctorate, Fred Hutchinson Cancer Research Center, Seattle, WA

Regulation of Pre-mRNA Splicing and Analysis of Small RNA Function and Biogenesis

Alternative Splicing Regulation and mRNA Stability
Research in our laboratory is focused on the regulation of alternative pre-mRNA splicing. We focus on the identification of the cis splicing-regulatory elements, the trans-acting protein factors that bind them, and the mechanisms by which splicing is regulated. Our laboratory is currently using powerful genetic tools to identify new regulatory interactions in the spliceosome that contribute to the selection of cryptic splice sites and provide clues to mechanisms behind splicing fidelity. We have also uncovered tissue-specific 3' splice site choice differences between somatic and germ cells and are exploring the basis of this tissue-specific regulation. We are using the powerful genetic, molecular biology, genome editing and bioinformatics tools available for the nematode Caenorhabditis elegans to tackle these problems.

Small RNA Function in Ciliated Protozoans
Ciliated protozoans possess two types of nuclei; a transcriptionally silent micronucleus, which serves as the germ line nucleus, and a transcriptionally active macronucleus, which serves as the somatic nucleus. The macronucleus is derived from a new diploid micronucleus after mating, with epigenetic information contributed by the parental macronucleus serving to guide the formation of the new macronucleus. In the stichotrichous ciliate Oxytricha trifallax, the macronuclear DNA is highly processed to yield gene-sized nanochromosomes with an average length of 2200bp - most nanochromosomes encode only one gene and there are ~20,000 genes in the organism. We study the role of small RNAs in the regulation of this process. We found that soon after mating of Oxytricha is initiated, abundant 27nt small RNAs are produced from the parental macronucleus, and are hypothesized to have an epigenetic role in guiding formation of a new macronucleus. Our most recent work is focused on analyzing all genes that are turned on during the complex events of macronuclear develop. We uncover important genes involved in DNA and RNA synthesis and regulation, suggestive of several mechanisms required for this complex process of genome generation, as well as an important role for gene duplication and specialization in this process.

Selected Publications

Zahler, A.M., Rogel, L.E., Glover, M.L., Yitiz, S., Ragle, J.M. and Katzman, S. 2018. SNRP-27, the C. elegans homolog of the tri-snRNP 27K protein, has a role in 5' splice site positioning in the spliceosome. RNA pii: rna.066878.118. doi: 10.1261/rna.066878.118.

Neeb, Z.T., Hogan, D.J., Katzman, S. and Zahler, A.M. 2017. Preferential expression of scores of functionally and evolutionarily diverse DNA and RNA-binding proteins during Oxytricha trifallax macronuclear development. PLoS ONE 12(2):e0170870.

Ragle, J.M., Katzman, S., Akers, T.F., Barberan-Soler, S. and Zahler, A.M. 2015. Coordinated tissue-specific regulation of alternative adjacent 3' splice sites in C. elegans. Genome Research 25: 982-94.

Zahler, A.M., Neeb, Z.T., Lin, A. and Katzman, S. 2012. Mating of the Stichotrichous Ciliate Oxytricha trifallax Induces Production of a Class of 27nt Small RNAs Derived from the Parental Macronucleus. PLoS One 7:e42371.

Zahler, A.M. 2012. Pre-mRNA splicing and its regulation in Caenorhabditis elegans, WormBook, ed. The C. elegans Research Community, WormBook, doi/10.1895/wormbook.1.31.2, Wormbook.

Lambert, N.J., Gu, S.G. and Zahler, A.M. 2011. The conformation of microRNA seed regions in native microRNPs is prearranged for presentation to mRNA targets. Nucleic Acids Research Nucleic Acids Res. 39: 4827-35.

Barberan-Soler, S., Medina, P., Estella, J., Williams, J. and Zahler, A.M. 2011. Co-regulation of alternative splicing by diverse splicing factors in Caenorhabditis elegans. Nucleic Acids Research 39: 666-674.

Kabat, J.L., Barberan-Soler, S. and Zahler, A.M. 2009. HRP-2, the C. elegans homolog of mammalian HNRNP Q and R, is an alternative splicing factor that binds to UCUAUC splicing regulatory elements. J. Biol. Chem. 284:28490-7.

Barberan-Soler, S., Lambert, N.J. and Zahler, A.M. 2009. Global analysis of alternative splicing uncovers developmental regulation of nonsense-mediated decay in C. elegans. RNA 15: 1652-1660.

Dassah, M., Patzek, S., Hunt, V.M., Medina, P.E. and Zahler A.M. 2009. A genetic screen for suppressors of a mutated 5' splice site identifies factors associated with later steps of spliceosome assembly. Genetics 182: 725-734.

Barberan-Soler, S. and Zahler, A.M. 2008. Alternative splicing and the steady-state ratios of mRNA isoforms generated by it are under strong stabilizing selection in C. elegans. Mol. Biol. Evol. 25:2341-2347.

Barberan-Soler, S. and Zahler, A.M. 2008. Alternative splicing regulation during C. elegans development: splicing factors as regulated targets. PLoS Genetics 4:e1000001.

Gu, S.G., Pak, J., Barberan-Soler, S., Ali, M., Fire, A., and Zahler, A.M. 2007. Distinct ribonucleoprotein reservoirs for microRNA and siRNA populations in C. elegans. RNA 13:1492-1504.

Kabat, J.L., Barberan-Soler, S., McKenna, P., Clawson, H., Farrer, T. and Zahler, A.M. 2006. Intronic alternative splicing regulators identified by comparative genomics in nematodes. PLoS Computational Biology 2:e86.

Kent, W.J., Sugnet, C.W., Furey, T.S., Roskin, K.M., Pringle, T.H., Zahler, A.M. and Haussler, D. 2002. The human genome browser at UCSC. Genome Research 12:996-1006.

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