Evolution of "Cilia Proteins" gene regulatory mechanisms
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Abstract
Eukaryotic cilia are evolutionarily conserved organelles that enable cellular motility and sensory functions and were present in the last eukaryotic common ancestor (LECA). Cilia are cell appendages composed of microtubules, emerging from a basal body that anchors the cilium within the cell, facilitating both movement and perception of external signals. While single-celled eukaryotes possess motile cilia that can also exhibit sensory functions, multicellular organisms exhibit two main types: motile cilia, aiding fluid transport, and immotile primary cilia, which serve as sensory signalling hubs for tissue development and homeostasis. Mutations in ciliary proteins lead to distinct clinical pathogenic phenotypes, stemming from impaired signalling in primary cilia or reduced motility of motile cilia. These classes of syndromes are termed ciliopathies, of which the Bardet-Biedl Syndrome (BBS) is considered the archetypical ciliopathy. The BBSome is a highly conserved octameric complex (BBS1, 2, 7, 9, 4, 8, 5, and 18) facilitating ciliary cargo transport by linking cargo proteins with transport complexes. Research in cilia biology has traditionally focussed on the roles of BBSome and chaperonin-like BBS proteins (BBS6, 10, 12 – required in the assembly of the BBsome) in cilia assembly. Recent findings hint at novel functions for ciliary proteins, including vesicular transport, mitotic regulation, and cytokinesis, and nuclear-associated tasks like chromatin modulation via histones, gene regulation via transcription factor transport, and epigenetic modifications via DNA methylation. In this thesis we comprehensively analysed human BBS protein nuclear localisation and their conservation across eukaryotes through phylogenetic reconstructions. We found that BBS proteins are highly conserved from LECA, and that some are even retained despite absence of other BBS proteins. By signal sequence prediction and permutation analysis, the propensity of BBS proteins to enter eukaryotic nuclei was assessed both across different taxa as well as different BBS proteins.We found that the ability to enter the nucleus is unaffected by mitotic nuclear envelope breakdown. Exploring potential gene regulatory roles, non-model organisms, in this case insects, were considered given their limited cilia expression as well as possible phenotypes linked to the regulatory roles of BBS proteins. Honeybees provide promising BBS protein candidates for influencing gene expression. Furthermore, this thesis examines the co-evolution of organelles during early eukaryogenesis by integrating insights into ciliary proteins, nuclear pore complexes, and karyopherins. This sheds light into potential processes that could have lead to the acquisition of nuclear functions during the transition to LECA, and provides a basis to identify possible conserved functions of BBS proteins in otherwise disparate eukaryotic organisms. With this work, we gained new insights into the evolution of nuclear localisation of BBS proteins across the entire eukaryotic Tree of Life. The results obtained have implications for evolutionary and developmental biology alike, as they highlight the versatility of ‘ciliary’ proteins to participate in diverse biological processes apart from ciliary transport. These new functions might help explain ciliopathy phenotypes and elucidate disease mechanisms, and aid in understanding early eukaryogenesis.