Biology subjects

Rasko, J. E. J.

Publications and source records attributed to Rasko, J. E. J..

3 recordsLinked to original sources

bioRxiv2022

Probing the evolutionary dynamics of whole-body regeneration within planarian flatworms

Why some animals can regenerate while many others cannot remains a fascinating question. Even amongst planarian flatworms, well-known for their ability to regenerate complete animals from small body fragments, species exist that have restricted regeneration abilities or are entirely regeneration incompetent. Towards the goal of probing the evolutionary dynamics of regeneration, we have assembled a diverse live collection of planarian species from around the world. The combined quantification of species-specific head regeneration abilities and comprehensive transcriptome-based phylogeny reconstructions reveals multiple independent transitions between robust whole-body regeneration and restricted regeneration in the freshwater species. Our demonstration that the RNAi-mediated inhibition of canonical Wnt signalling can nevertheless bypass all experimentally tractable head regeneration defects in the current collection indicates that the pathway may represent a hot spot in the evolution of planarian regeneration defects. Combined with our finding that Wnt signalling has multiple roles in the reproductive system of the model species S. mediterranea, this raises the possibility of a trade-off between egg-laying and asexual reproduction by fission/regeneration as a driver of regenerative trait evolution. Although initial quantitative comparisons of Wnt signalling levels, reproductive investment, and regenerative abilities across the collection confirm some of the models predictions, they also highlight the diversification of molecular mechanisms amongst the divergent planarian lineages. Overall, our study establishes a framework for the mechanistic evolution of regenerative abilities and planarians as model taxon for comparative regeneration research.

evolutionary biology↗

bioRxiv2022

Towards resolution of the intron retention paradox in breast cancer

After many years of neglect in the field of alternative splicing, the importance of intron retention (IR) in cancer has come into focus following landmark discoveries of aberrant IR patterns in cancer. Many solid and liquid tumours are associated with drastic increases in IR and such patterns have been pursued as both biomarkers and therapeutic targets. Paradoxically, breast cancer (BrCa) is the only tumour type in which IR is reduced compared to adjacent normal breast tissue. In this study, we have conducted a pan-cancer analysis of IR with emphasis on BrCa and its subtypes. We explored mechanisms that could cause aberrant and pathological IR and clarified why normal breast tissue has unusually high IR. Strikingly, we found that reduced IR in BrCa can be largely attributed to normal breast tissue having the highest occurrence of IR events compared to other healthy tissues. Our analyses suggest that low numbers of IR events in breast tumours are associated with poor prognosis, particularly in the luminal B subtype. Interestingly, we found that IR frequencies negatively correlate with cell proliferation in BrCa cells, i.e. rapidly dividing tumour cells have the lowest number of IR events. Aberrant RNA binding protein (RBP) expression and changes in tissue composition are among the causes of low IR in BrCa. Our results suggest that IR should be considered for therapeutic manipulation in BrCa patients with aberrantly low IR levels and that further work is needed to understand the cause and impact of high IR in other tumour types.

cancer biology↗

bioRxiv2021

Unique Protein Interaction Networks Define The Chromatin Remodeling Module of The NuRD Complex

The combination of four proteins and their paralogues including MBD2/3, GATAD2A/B, CDK2AP1, and CHD3/4/5, which we refer to as the MGCC module, form the chromatin remodeling module of the Nucleosome Remodeling and Deacetylase (NuRD) complex, a gene repressor complex. Specific paralogues of the MGCC subunits such as MBD2 and CHD4 are amongst the key repressors of adult-stage fetal globin and provide important targets for molecular therapies in beta ({beta})-thalassemia. However, mechanisms by which the MGCC module acquires paralogue-specific function and specificity have not been addressed to date. Understanding the protein-protein interaction (PPI) network of the MGCC subunits is essential in defining underlying mechanisms and developing treatment strategies. Therefore, using pulldown followed by mass spectrometry analysis (PD-MS) we report a proteome-wide interaction network of the MGCC module in a paralogue-specific manner. Our data also demonstrate that the disordered C-terminal region of CHD3/4/5 is a gateway to incorporate remodeling activity into both the ChAHP (CHD4, ADNP, HP1{gamma}) and NuRD complexes in a mutually exclusive manner. We define a short aggregation prone region (APR) within the C-terminal segment of GATAD2B that is essential for the interaction of CHD4 and CDK2AP1 with the NuRD complex. Finally, we also report an association of CDK2AP1 with the Nuclear Receptor Co-Repressor (NCOR) complex. Overall, this study provides insight into the possible mechanisms through which the MGCC module can achieve specificity and diverse biological functions.

biochemistry↗