Biology subjects

Zajkowski, T.

Publications and source records attributed to Zajkowski, T..

3 recordsLinked to original sources

bioRxiv2022

Universal functions of prion candidates across all three domains of life suggest a primeval role of protein self-templating.

Amyloid-based prions have simple structures, a wide phylogenetic distribution, and a plethora of functions in contemporary organisms, suggesting they may be an ancient phenomenon. However, this hypothesis has yet to be addressed with a systematic, computational, and experimental approach. Here we present a framework to help guide future experimental verification of candidate prions with conserved functions in order to understand their role in the early stages of evolution and potentially in the origins of life. We identified candidate prions in all high-quality proteomes available in UniProt computationally, assessed their phylogenomic distributions, and analyzed candidate-prion functional annotations. Of the 27,980,560 proteins scanned, 228,561 were identified as candidate prions ([~]0.82%). Among these candidates, there were 84 Gene Ontology (GO) terms conserved across the 3 domains of life. We found that candidate prions with a possible role in adaptation were particularly well-represented within this group. We discuss unifying features of candidate prions to elucidate the primeval roles of prions and their associated functions. Candidate prions annotated as transcription factors, DNA binding, and kinases are particularly well suited to generating diverse responses to changes in their environment and could allow for adaptation and population expansion into more diverse environments. We hypothesized that these functions could be evolutionarily ancient, even if individual prion domains themselves are not evolutionarily conserved. Candidate prions annotated with these universally-occurring functions potentially represent the oldest extant prions on Earth and are therefore excellent experimental targets.

bioinformatics↗

bioRxiv2020

The hunt for ancient prions: Archaeal prion-like domains form amyloids and substitute for yeast prion domains

Prions are proteins capable of acquiring an alternate conformation that can then induce additional copies to adopt this same alternate conformation. Although initially discovered in relation to mammalian disease, subsequent studies have revealed the presence of prions in Bacteria and Viruses, suggesting an ancient evolutionary origin. Here we explore whether prions exist in Archaea - the last domain of life left unexplored with regard to prions. After searching for potential prion-forming protein sequences computationally, we tested candidates in vitro and in organisms from the two other domains of life: Escherichia coli and Saccharomyces cerevisiae. Out of the 16 candidate prion-forming domains tested, 8 bound to amyloid-specific dye, and six acted as protein-based elements of information transfer, driving non-Mendelian patterns of inheritance. We additionally identified short peptides from archaeal prion candidates that can form amyloid fibrils independently. Candidates that tested positively in our assays had significantly higher tyrosine and phenylalanine content than candidates that tested negatively, suggesting that the presence of these amino acids may help distinguish functional prion domains from nonfunctional ones. Our data establish the presence of amyloid-forming prion-like domains in Archaea. Their discovery in all three domains of life further suggests the possibility that they were present at the time of the last universal common ancestor (LUCA). Significance StatementThis work establishes that amyloid-forming, prion-like domains exist in Archaea and are capable of vertically transmitting their prion phenotype - allowing them to function as protein-based elements of inheritance. These observations, coupled with prior discoveries in Eukarya and Bacteria, suggest that prion-based self-assembly was likely present in lifes last universal common ancestor (LUCA), and therefore may be one of the most ancient epigenetic mechanisms.

evolutionary biology↗

bioRxiv2019

The transcription factor TCF7L2 functions as a terminal selector in thalamic and habenular regions of the brain

Neuronal phenotypes are controlled by terminal selector transcription factors in invertebrates, but few examples of such regulators have been provided in vertebrates. TCF7L2 has been identified as a regulator of efferent outgrowth in the thalamus and habenula. We used a complete and conditional knockout of Tcf7l2 in mice to investigate the hypothesis that TCF7L2 plays a dual role in thalamic neuron differentiation and functions as a terminal selector. Connectivity and cell clustering was disrupted in the thalamo-habenular region in Tcf7l2-/- embryos. The expression of subregional thalamic and habenular transcription factors was lost and region-specific cell migration and axon guidance genes were downregulated. In mice with postnatal Tcf7l2 knockout, the induction of genes that confer terminal electrophysiological features of thalamic neurons was impaired. Many of these genes proved to be TCF7L2 direct targets. The role of TCF7L2 in thalamic terminal selection was functionally confirmed by impaired firing modes in thalamic neurons in the mutant mice. These data corroborate the existence of master regulators in the vertebrate brain that maintain regional transcriptional network, control stage-specific genetic programs and induce terminal selection. StatementThe study describes a role of TCF7L2 in neuronal differentiation of thalamic glutamatergic neurons at two developmental stages, highlighting its involvement in the postnatal establishment of critical thalamic electrophysiological features.

developmental biology↗