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Co-option of cilia proteins in gene regulatory processes

Supervisor: Helen May-Simera

Co-Supervisor: Susanne Foitzik, Susanne Gerber


Scientific Background:
Cilia and flagella are present widely across eukaryotic lineages and evolved to serve a multitude of functions, from locomotion and chemotaxis in unicellular green algae to reception of light in animals. Although their functions vary, many proteins required to build and maintain these structures are conserved across species. More recently, however, ciliary proteins have been found to localise to other cellular compartments where they may function in non-ciliary processes. These have most likely arisen via a process of co-option. The BBS proteins (A) are a special class of ciliary trafficking proteins. The BBSome is a heterooctameric complex and serves as a cargo adaptor during ciliary trafficking, whilst the so-called chaperonin-like BBS proteins aid in the assembly of the BBSome complex itself. In addition to functions in ciliary trafficking and protein folding, some BBS proteins have recently been associated with components of gene regulatory networks and DNA damage response. Just recently BBS4 was shown to be required for nuclear transport of transcription factors.

In the first GenEvo period, we identified orthologous BBS proteins across a diverse phylogenetic spectrum (B) and bioinformatically predicted the presence of putative nuclear localization or nuclear exit signals (NES/NLS). Importantly, these seem to have evolved independently of the mode of mitosis, which may suggest an evolutionary selected active process.


PhD project: Co-option of cilia proteins in gene regulatory processes
The second GenEvo period addresses two main questions. Q1) Is stress-related nuclear import also a feature of BBS proteins outside of animals? Q2) What is the consequence of BBS protein re-localization to the nucleus and how do they influence gene regulatory functions in animal and non-animal cells? To address Q1 we will tag BBS proteins in cells from diverse eukaryotic lineages (Tetrahymena, Chlamydomonas, Trypanosoma, Dictyostelium) and test their nuclear localization upon various treatments. To address Q2 we will adopt two main approaches. First, a proteomic approach in which we will identify the BBS nuclear interactome via co-immunoprecipitation of tagged BBS proteins from nuclear fractions and subsequent Mass Spectrometry. Second a transcriptomic approach in which we will overexpress BBS proteins in the nucleus and look for changes in gene regulation and expression.


Publications relevant to this project
Horwitz A, Birk R. BBS4 Is Essential for Nuclear Transport of Transcription Factors Mediating Neuronal ER Stress Response. Mol Neurobiol. 2021 Jan;58(1):78-91.
Scott, C. A. et al. Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein. PLOS Genet. 13, e1006936 (2017).
Gascue, C. et al. Direct role of Bardet-Biedl syndrome proteins in transcriptional regulation. J. Cell Sci. 125, 362–375 (2012).
Ramachandran, H. et al. Interaction with the Bardet-Biedl gene product TRIM32/BBS11 modifies the half-life and localization of Glis2/NPHP7. J. Biol. Chem. 289, 8390–401 (2014).