Prof. Gil Ast

Professor, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University

Alternative Splicing Generates Transcriptomic Diversity in Genetic Disorders & Cancer

By utilizing the unique strengths of our research group in bioinformatic analyses as well as in genomic and advanced molecular biology methodologies, we are able to make groundbreaking discoveries in the field of alternative splicing. We study how alternative splicing generates higher level of organism complexity, especially in human. However, this comes with a price, and alternative splicing also inflicts many genetic disorders and cancer.

Our research involves these two facets of alternative splicing. On one hand, we found how new functions evolved via the generation of new exons (mostly in human). We have also showed how different layers of gene expression affect each other, and found that chromatin organization and epigenetic markers (DNA methylation) mark the exon-intron structure. We also found that during the evolution of warm-blooded organisms two exon-intron gene architectures developed, and these also reflect the different effects of mutations on splicing in cancer and other genetic disorders. On the other hand, we study the impact of splicing abnormalities on colon and lung cancer, and we have recently discovered a new therapy for Familial Dysautonomia, a neurodegenerative disease caused by a splicing defect in the nervous system.

Publications

Fuchs G, Hollander D, Voichek Y, Ast G, Oren M. (2014) Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate. Genome Res. 24:1572-83.

Gelfman S, Ast G. When epigenetics meets alternative splicing. (2013) The roles of DNA methylation and GC architecture. Epigenomics. 2013:351-353.

Melamed Z, Levy A, Ashwal-Fluss R, Lev-Maor G, Mekahel K, Atias N,  Gilad S,  Sharan R,  Levy C,  Kadener S, Ast G. Alternative splicing regulates biogenesis of miRNAs located across exon-intron junctions. (2013). Mol Cell, 50:869-881.

Bochner R, Ziv Y, Zeevi D, Donyo M, Abraham L, Ashery-Padan R, Ast G. Phosphatidylserine increases IKBKAP levels in a humanized knock-in IKBKAP mouse model. (2013) Hum Molec Genet. 22: 2785-2794

Gelfman S, Cohen N, Yearim A, Ast G. DNA-methylation effect on cotranscriptional splicing is dependent on GC architecture of the exon-intron structure. (2013) Genome Res. 23:789-799.

Amit M, Donyo M, Hollander D, Goren A, Kim E, Gelfman S, Lev-Maor G, Burstein D, Schwartz S, Postolsky B, Pupko P, Ast G. (2012) Differential GC content between exons and introns establishes distinct strategies of splice site recognition. Cell Reports, 1:543-556.

Gelfman S, Burstein D, Penn O, Savchenko A, Amit M, Schwartz S, Pupko T, Ast G. (2012) Changes in exon-intron structure during vertebrate evolution affect the splicing pattern of exons. Genome Res 22:35-50.

Cheishvili D, Maayan C, Cohen-Kupiec R, Lefler S, Weil M, Ast G, Razin A. (2011) IKAP/Elp1 involvement in cytoskeleton regulation and implication for familial dysautonomia. Hum Mol Genet. 20:1585-1594.

Keren H., Donyo M., Zeevi D., Maayan, C., Pupko, T. and Ast G. (2010) Phosphatidylserine increases IKBKAP levels in Familial Dysautonomia Cells. PloS One, 5:e15884.

Llorian, M., Schwartz, S., Clark, T. A., Hollander, D., Tan, L., Spellman, R., Gordon, A., Schweitzer, A. C., de la Grange, P., Ast, G., and Smith, C. (2010) Position-dependent alternative splicing activity revealed by global profiling of alternative splicing events regulated by PTB. Nature Struct Mol Biol. 17:1114-23.

Sela N, Mersch B, Hotz-Wagenblatt A, Ast G. (2010) Characteristics of transposable element exonization within human and mouse. PLoS One. 5:e10907.

Sela N, Kim E, Ast G. (2010) The role of transposable elements in the evolution of non-mammalian vertebrates and invertebrates. Genome Biol. 11:R59.

Goren A, Kim E, Amit M, Vaknin K, Kfir N, Ram O, Ast G. (2010) Overlapping splicing regulatory motifs--combinatorial effects on splicing. Nucleic Acids Res. 38:3318-3327.

Asaf Levy, Schraga Schwartz and Ast G. (2010) Insertion hotspots and nepotism of DNA parasites: large-scale analysis of human nested transposed elements. Nucleic Acids Res. 38:1515-1530.

Reviews

Gelfman S, Ast G. (2013) When epigenetics meets alternative splicing: the roles of DNA methylation and GC architecture. Epigenomics. 5:351-3

Schraga Schwartz and Ast G. (2010) Chromatin density and splicing destiny: on the cross-talk between chromatin structure and splicing. EMBO J. 29:1629–1636.

Keren H, Lev-Maor G, Ast G. (2010) Alternative splicing and evolution: diversification, exon definition and function. Nature Rev Genet. 11:345-355.

Grants

2012-2015       ISF- Morasha for Neurodegenerative Diseases, Tissue-specific alternative splicing disease

2013-2015       Teva – Neuroscience, Evaluation of therapeutic agents in a mouse model for Familial Dysotonomia

2013-2018       Israel Science Foundation, Identification of novel determinants of splicing regulation

2014-2015       Israel Cancer Research Fund (ICRF) Project Grant