Zahler, Alan - University of California, Santa Cruz - Molecular, Cell & Developmental Biology Faculty

个人简介

B.S., Carnegie-Mellon University Ph.D., University of Colorado, Boulder Postdoctorate, Fred Hutchinson Cancer Research Ctr, Seattle, WA.

研究领域

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 alternative splicing code; the sequences on the pre-mRNA and the protein factors that bind to them which regulate alternative splicing. We have focused 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 using the powerful genetic, molecular biology and bioinformatics tools available for the nematode Caenorhabditis elegans to tackle this problem. A recent area of focus is the connection between alternative splicing and message stability. In about 1/3 of cases, alternative splicing yields an isoform with a premature stop codon; this isoform is unstable and subject to nonsense-mediated mRNA decay. We have identified many examples of alternative splicing factors whose own expression is regulated by alternative splicing coupled to nonsense-mediated decay. We are characterizing this process in C. elegans where we have uncovered a phenomenon in which the efficiency of nonsense-mediated decay can be developmentally regulated. 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 %7e20,000 genes in the organism. We recently started to use this system to study the role of small RNAs in the regulation of chromatin. We found that soon after mating of Oxytricha is initiated, abundant 27nt small RNAs are produced that are not present prior to mating. We performed next generation sequencing of these small RNAs and found that the 27nt RNA class derives from the parental macronucleus. These small RNAs are produced equally from both strands of macronuclear nanochromosomes, but in a non-uniform distribution along the length of the nanochromosome, with a particular depletion in the 30 nt telomere-proximal positions. We are currently studying the mechanism by which the entire macronuclear genome is transcribed and processed into short RNAs and the role of these "27macRNAs" in macronuclear development.

近期论文

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Prp8 impacts cryptic but not alternative splicing frequency. Mayerle M, Yitiz S, Soulette C, Rogel LE, Ramirez A, Ragle JM, Katzman S, Guthrie C, Zahler AM. Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2193-2199. doi: 10.1073/pnas.1819020116. Epub 2019 Jan 23. SNRP-27, the C. elegans homolog of the tri-snRNP 27K protein, has a role in 5' splice site positioning in the spliceosome. Zahler AM, Rogel LE, Glover ML, Yitiz S, Ragle JM, Katzman S. RNA. 2018 Oct;24(10):1314-1325. doi: 10.1261/rna.066878.118. Epub 2018 Jul 13. Preferential expression of scores of functionally and evolutionarily diverse DNA and RNA-binding proteins during Oxytricha trifallax macronuclear development. Neeb ZT, Hogan DJ, Katzman S, Zahler AM. PLoS One. 2017 Feb 16;12(2):e0170870. doi: 10.1371/journal.pone.0170870. eCollection 2017. Coordinated tissue-specific regulation of adjacent alternative 3' splice sites in C. elegans. Ragle JM, Katzman S, Akers TF, Barberan-Soler S, Zahler AM. Genome Res. 2015 Jul;25(7):982-94. doi: 10.1101/gr.186783.114. Epub 2015 Apr 28. An expanding world of small RNAs. Neeb ZT, Zahler AM. Dev Cell. 2014 Jan 27;28(2):111-2. doi: 10.1016/j.devcel.2014.01.009. Mating of the stichotrichous ciliate Oxytricha trifallax induces production of a class of 27 nt small RNAs derived from the parental macronucleus. Zahler AM, Neeb ZT, Lin A, Katzman S. PLoS One. 2012;7(8):e42371. doi: 10.1371/journal.pone.0042371. Epub 2012 Aug 10. Pre-mRNA splicing and its regulation in Caenorhabditis elegans. Zahler AM. WormBook. 2012 Mar 21:1-21. doi: 10.1895/wormbook.1.31.2. Review. The conformation of microRNA seed regions in native microRNPs is prearranged for presentation to mRNA targets. Lambert NJ, Gu SG, Zahler AM. Nucleic Acids Res. 2011 Jun;39(11):4827-35. doi: 10.1093/nar/gkr077. Epub 2011 Feb 18.