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Biology subjects

Mateos, B.

Publications and source records attributed to Mateos, B..

4 recordsLinked to original sources

Silencing of a raspberry homologue of VRN1 is associated with disruption of dormancy induction and misregulation of subsets of dormancy-associated genes.

Winter dormancy is a key process in the phenology of temperate perennials. The changing climate is severely impacting its course leading to economic losses in agriculture. A better understanding of the underlying mechanisms, as well as the genetic basis of the different responses, are necessary for the development of climate-resilient cultivars. This study aims to provide an insight into winter dormancy in red raspberry (Rubus idaeus L). We report the transcriptomic profiles during dormancy in two raspberry cultivars with contrasting responses. The cultivar Glen Ample showed a typical perennial phenology, whereas Glen Dee registered consistent dormancy dysregulation, exhibiting active growth and flowering out of season. RNA-seq combined with weighted gene co-expression network analysis (WGCNA) highlighted gene clusters in both genotypes that exhibited time-dependent expression profiles, Functional analysis of Glen Ample gene clusters highlighted the significance of the cell and structural development prior to dormancy entry as well the role of genetic and epigenetic processes such as RNAi and DNA methylation in regulating gene expression. On the contrary, dormancy release in Glen Ample was associated with upregulation of transcripts associated with the resumption of metabolism, nucleic acid biogenesis and processing signal response pathways. Many of the processes occurring in Glen Ample were dysregulated in Glen Dee and twenty-eight transcripts exhibiting time-dependent expression in Ample that also had an Arabidopsis homologue were not found in all samples from Glen Dee. These included a gene with homology to Arabidopsis VRN1 (RiVRN1.1) that exhibited a sharp decline in expression following dormancy induction in Glen Ample. Characterisation of the gene region in the Glen Dee genome revealed two large insertions upstream of the ATG start codon. We propose that non-expression of a specific VRN1 homologue in Glen Dee causes dormancy misregulation as a result of inappropriate expression of a subset of genes that are directly or indirectly regulated by RiVRN1.1. HIGHLIGHTThe raspberry cultivar Glen Dee exhibits aberrant winter dormancy status associated with insertions in the upstream promoter region of a VRN1 (RiVRN1.1) homologue that silence expression, allowing the identification of dormancy-associated genetic modules that are regulated by RiVRN1.1.

plant biology↗

Targeting the BAG-1 family of co-chaperones in lethal prostate cancer.

Therapies that abrogate persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain (NTD) of the AR drives transcriptional activity in CRPC but is intrinsically disordered and remains a challenging therapeutic target. Therefore, inhibiting critical co-chaperones, such as BAG-1L, is an attractive alternative strategy. We performed druggability analyses demonstrating the BAG domain to be a challenging drug target. Thio-2, a tool compound, has been reported to bind the BAG domain of BAG-1L and inhibit BAG-1L-mediated AR transactivation. However, despite these data, the mechanism of action of Thio-2 is poorly understood and the BAG domain which is present in all BAG-1 isoforms has not been validated as a therapeutic target. Herein, we demonstrate growth inhibiting activity of Thio-2 in CRPC cell lines and patient derived models with decreased AR genomic binding and AR signaling independent of BAG-1 isoform function. Furthermore, genomic abrogation of BAG-1 isoforms did not recapitulate the described Thio-2 phenotype, and NMR studies suggest that Thio-2 may bind the AR NTD, uncovering a potential alternative mechanism of action, although in the context of low compound solubility. Furthermore, BAG-1 isoform knockout mice are viable and fertile, in contrast to previous studies, and when crossed with prostate cancer mouse models, BAG-1 deletion does not significantly impact prostate cancer development and growth. Overall, these data demonstrate that Thio-2 inhibits AR signaling and growth in CRPC independent of BAG-1 isoforms, and unlike previous studies of the activated AR, therapeutic targeting of the BAG domain requires further validation before being considered a therapeutic strategy for the treatment of CRPC.

molecular biology↗

Androgen receptor condensates as drug targets

Transcription factors are among the most attractive therapeutic targets but are considered largely undruggable due to the intrinsically disordered nature of their activation domains. Here we show that the aromatic character of the activation domain of the androgen receptor, a therapeutic target for castration resistant prostate cancer, is key for its activity as a transcription factor by allowing it to partition into transcriptional condensates. Based on this knowledge we optimized the structure of a small molecule inhibitor, previously identified by phenotypic screening, that targets a specific transactivation unit within the domain that is partially folded and rich in aromatic residues. The optimized compounds had more affinity for their target, inhibited androgen receptor-dependent transcriptional programs, and had antitumorigenic effect in models of castration-resistant prostate cancer in cells and in vivo. These results establish a generalizable framework to target small molecules to the activation domains of oncogenic transcription factors and other disease-associated proteins with therapeutic intent.

biochemistry↗

A rigidity phase transition of Stomatin condensates governs a switch from transport to mechanotransduction

A large body of work suggests that biomolecular condensates ensuing from liquid-liquid phase separation mature into various material states. How this aging process is controlled and if the naive and mature phases can have differential functions is currently unknown. Using Caenorhabditis elegans as a model, we show that MEC-2 Stomatin undergoes a rigidity phase transition during maturation from fluid to viscoelastic, glass-like condensates that facilitate either transport or mechanotransduction. This switch is promoted by the SH3 domain of UNC-89/Titin/Obscurin through a direct interaction with MEC-2 and suggests a physiological role for a percolation transition in force transmission during body wall touch. Together, our data demonstrate a novel function for rigidity maturation during mechanotransduction and a previously unidentified role for Titin homologs in neurons.

cell biology↗