Recent studies carried out in a wide range of eukaryotic organisms indicate that more than 90% of the eukaryotic genome is transcriptionally active, and a large portion of the transcriptome consists of non-protein-coding RNA transcripts (ncRNAs
or cryptic transcripts
). Transcription of ncRNAs is linked to key chromosomal events such as chromatin remodeling, gene regulation and establishment of heterochromatic domains, but the function and significance of the widespread ncRNA transcription is not understood. While coding RNAs are packaged and exported from the nucleus, the majority of cryptic transcripts are recognized and quickly degraded by the RNA surveillance machinery
. Defects in the recognition and degradation of cryptic transcripts or increased transcriptional activity outside of the genetically confined transcription units can lead to toxic accumulation of these transcripts and cause genomic instability and chromosome segregation defects.
The major goals of the research in our laboratory are:
i) to identify the epigenetic mechanisms
responsible for accurate definition of transcription units and their transcripts, and to understand how these mechanisms are involved in controlling ncRNA transcription
ii) to understand how epigenetic processes control genomic stability
and chromosome segregation
Our methodology includes traditional genetic, molecular biology and biochemical techniques combined with modern genomic methods, including high-throughput sequencing, tiling arrays and bioinformatics tools. We are using various yeast and mammalian cell culture systems as models.
Accumulating evidence suggests that RNA plays a much more significant role in nuclear processes than previously imagined. These studies will significantly increase our general understanding of genome organization
and transcriptional regulation
, and the biological significance of the recently described variety of ncRNAs in the eukaryotic cell. Mutations leading to genomic instability are a major cause of cancer development
and contribute to an enhanced mutation rate in cancer cells. Increased understanding of the molecular mechanisms behind these processes will advance the development of preventive and corrective treatments for malignant cancers.
Zhou, Y.*, Zhu, J.*, Schermann, G., Ohle, C., Bendrin, K., Sugioka-Sugiyama, R., Sugiyama, T., and Fischer, T. (2015). The fission yeast MTREC complex targets CUTs and unspliced pre-mRNAs to the nuclear exosome. Nat. Commun. 7:7050 (*These authors contributed equally.)
Sancar, C., Ha, N., Yilmaz, R., Tesorero, R., Fischer, T., Brunner, M., Sancar, G. (2015) Combinatorial control of light induced chromatin remodeling and gene activation in neurospora. PLoS Genet 3:e1005105
Hoffmann, J., Symul, L., Shostak, A., Fischer, T., Naef, F., Brunner, M. (2014) Non-Circadian expression masking clock-driven weak transcription rhythms in U2OS cells. PLoS One 7:e102238
Hennig, B.P., and Fischer, T. (2013) The great repression: Chromatin and cryptic transcription. Transcription 3: 97-101 (Review)
Hennig, B.P., Bendrin, K., Zhou, Y., and Fischer, T. (2012). Chd1 chromatin remodelers maintain nucleosome organization and repress cryptic transcription. EMBO Rep 13, 997-1003.
Zhang, K., Fischer, T., Porter, R.L., Dhakshnamoorthy, J., Zofall, M., Zhou, M., Veenstra, T., and Grewal, S.I. (2011). Clr4/Suv39 and RNA quality control factors cooperate to trigger RNAi and suppress antisense RNA. Science 331, 1624-27.
Zofall, M.*, Fischer, T.*, Zhang, K., Zhou, M., Cui, B., Veenstra, T.D., and Grewal, S.I. (2009). Histone H2A.Z cooperates with RNAi and heterochromatin factors to suppress antisense RNAs. Nature 461, 419-422. (*These authors contributed equally.)
Fischer, T., Cui, B., Dhakshnamoorthy, J., Zhou, M., Rubin, C., Zofall, M., Veenstra, T.D., and Grewal, S.I. (2009). Diverse roles of HP1 proteins in heterochromatin assembly and functions in fission yeast. Proc Natl Acad Sci U S A 106, 8998-9003.
Jani, D., Lutz, S., Marshall, N.J., Fischer, T., Kohler, A., Ellisdon, A.M., Hurt, E., and Stewart, M. (2009). Sus1, Cdc31, and the Sac3 CID region form a conserved interaction platform that promotes nuclear pore association and mRNA export. Mol Cell 33, 727-737.
Roguev, A., Bandyopadhyay, S., Zofall, M., Zhang, K., Fischer, T., Collins, S.R., Qu, H., Shales, M., Park, H.O., et al. (2008). Conservation and rewiring of functional modules revealed by an epistasis map in fission yeast. Science 322, 405-410.
Grund, S.E., Fischer, T., Cabal, G.G., Antunez, O., Perez-Ortin, J.E., and Hurt, E. (2008). The inner nuclear membrane protein Src1 associates with subtelomeric genes and alters their regulated gene expression. J Cell Biol 182, 897-910.
Fischer, T., Rodriguez-Navarro, S., Pereira, G., Racz, A., Schiebel, E., and Hurt, E. (2004). Yeast centrin Cdc31 is linked to the nuclear mRNA export machinery. Nat Cell Biol 6, 840-48.
Rodriguez-Navarro, S., Fischer, T., Luo, M.J., Antunez, O., Brettschneider, S., Lechner, J., Perez-Ortin, J.E., Reed, R., and Hurt, E. (2004). Sus1, a functional component of the SAGA histone acetylase complex and the nuclear pore-associated mRNA export machinery. Cell 116, 75-86.
Olasz, F., Fischer, T., Szabo, M., Nagy, Z., and Kiss, J. (2003). Gene conversion in transposition of Escherichia coli element IS30. J Mol Biol 334, 967-978.
Fischer, T.*, Strasser, K.*, Racz, A., Rodriguez-Navarro, S., Oppizzi, M., Ihrig, P., Lechner, J., and Hurt, E. (2002). The mRNA export machinery requires the novel Sac3p-Thp1p complex to dock at the nucleoplasmic entrance of the nuclear pores. EMBO J 21, 5843-852. (*These authors contributed equally.)
Czirják, G., Fischer, T., Spät, A., Lesage, F., and Enyedi, P. (2000). TASK (TWIK-related acid-sensitive K+ channel) is expressed in glomerulosa cells of rat adrenal cortex and inhibited by angiotensin II. Mol Endocrinol 14, 863-874.