Department of Biochemistry University of Oxford Department of Biochemistry
University of Oxford
South Parks Road
Oxford OX1 3QU

Tel: +44 (0)1865 613200
Fax: +44 (0)1865 613201
Image showing the global movement of lipids in a model planar membrane
Matthieu Chavent, Sansom lab
Anaphase bridges in fission yeast cells
Whitby lab
Lactose permease represented using bending cylinders in Bendix software
Caroline Dahl, Sansom lab
Epithelial cells in C. elegans showing a seam cell that failed to undergo cytokinesis
Serena Ding, Woollard lab
Collage of Drosophila third instar larva optic lobe
Lu Yang, Davis lab
First year Biochemistry students at a practical class
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Lidia Vasilieva
Transcriptional and post-transcriptional regulation of gene expression in eukaryotes

Co-workers: Katie Duckett, Dong-Hyuk Heo, Tea Kecman, Krzysztof Kus, Dogukan Ulgen, Sina Wittmann, Beth Watts and Anna Wiecek

RNAs are involved in many key cellular processes, and even minor alterations in RNA level are often detrimental and could lead to diseases in human. Our research is aimed to understand how chromatin modifiers, RNA polymerase II transcription factors and the exosome complex, a major RNA processing/degradation machinery orchestrate different aspects of RNA metabolism: transcription, RNA processing and RNA quality control. To achieve this our laboratory is using multidisciplinary approaches where we combine state-of-the-art biochemistry, genetics and genomics to uncover molecular mechanisms regulating levels of individual transcripts in eukaryotes.

We are focused on two central questions:

  1. How does phosphorylation of the RNA polymerase II (Pol II) control gene expression?

Phosphorylation of the C-terminal domain (CTD) of the largest subunit of Pol II is fundamental to regulation of transcription and production of functional RNA, however the mechanisms underpinning CTD function remain obscure.

Recently, we have discovered that conserved proteins (Figure 1) that interact with both CTD and nascent RNA via CTD-Interacting-Domain (CID) and RNA-Recognition Motif (RRM) (Figure 2) are key to mediate CTD function. Building up on this exciting findings we now investigate how these essential proteins regulate transcription and RNA processing.

  1. How are individual transcripts targeted for degradation?

RNA exosome complex of 10-11 subunits that possesses 3’-5’ exo- and endonucleolytic activity is central to RNA regulation where it plays a key role in nearly every step of RNA metabolism including RNA maturation, degradation and surveillance (Figure 3). It controls expression levels of specific mRNAs in response to environmental cues, during cell differentiation and development. Although the mechanisms by which RNA is targeted to (or escapes from) the exosome are still not fully understood. In the past, we have identified RNA-binding proteins that regulate targeting of the exosome complex to specific RNAs (Exosome-Specificity-Factors, ESFs). One of our current goal is to understand how ESF regulate exosome targeting to the RNAs.

Publications

  1. Wittmann, S., Renner, M., Watts, B.R., Adams, O., Huseyin, M., Baejen, C., El Omari, K., Kilchert, C., Heo, D.H., Kecman, T., Cramer, P., Grimes, J.M., and Vasiljeva, L (2017) The conserved protein Seb1 drives transcription termination by binding RNA polymerase II and nascent RNA. Nature Communications. 8, 14861 doi: 10.1038/ncomms14861.
  2. Kilchert C, Wittmann S, Vasiljeva L.(2016) The regulation and functions of the nuclear RNA exosome complex. Nature Rev Mol Cell Biol. 17, 227-39. 
  3. Kilchert C, Wittmann S, Passoni M, Shah S, Granneman S, Vasiljeva L.(2015)Regulation of mRNA Levels by Decay-Promoting Introns that Recruit the Exosome Specificity Factor Mmi1. Cell Report. 22;13, 2504-15.
  4. Shah, S., Kilchert, C., Wittmann, S., and Vasiljeva, L. (2014) ‘lncRNA recruits RNAi and the exosome to dynamically regulate pho1 expression in response to phosphate levels in fission yeast’ Genes and Development 28, 231-244.
  5. Volanakis, A., Passoni, M., Hector, R., Kilchert, C., Shah, S., Granneman, S., and Vasiljeva, L. (2013) Spliceosome-Mediated-Decay (SMD) regulates expression of non-intronic genes in budding yeast. Genes and Development  27, 2025-38. 
More Publications...

Research Images

Figure 1: Conserved CID-RRM proteins in RNA polymerase II transcription. CID- CTD –Interacting –Domain, RRM- RNA Recognition Motif.
 

 

Figure 2: Novel organization of the RNA-binding module of CID-RRM proteins that consists of the canonical RRM and RRM-like domain (shown in green) (Wittmann et al., 2017 Nature Comm).
 

Figure 3: RNA exosome complex. The six-subunit RNAse PH-like ring (Rrp41, Rrp45, Rrp42, Mtr3, Rrp43, and Rrp46) assembles with three cap proteins (Csl4, Rrp4, and Rrp40) containing S1/KH domains into a nine-subunit core. Catalytic subunits Rrp44 (Dis3) (shown in yellow) and Rrp6 associates with the core (Kilchert et al., 2016 Nature Rev Mol Cell Biol).


In the news:

Our recent paper discovering a key role for conserved factors in terminating RNA polymerase II transcription:
http://www.bioch.ox.ac.uk/about/newsarchive/how-a-group-of-conserved-proteins-orchestrate-transcription-termination-in-eukaryotes

Our paper describing novel mechanism of regulation via splicing:
http://www.bioch.ox.ac.uk/about/archives2013/splicing-surprise-for-yeast-researchers

Contact: lidia.vasilieva@bioch.ox.ac.uk
Graduate Student and Postdoctoral Positions: Enquiries with CV welcome