Biology subjects

Reginato, M.

Publications and source records attributed to Reginato, M..

4 recordsLinked to original sources

bioRxiv2024

ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells

Brain metastasis diagnosis in breast cancer patients is considered an end-stage event. The median survival after diagnosis is measured in months, thus there is an urgent need to develop novel treatment strategies. Breast cancers that metastasize to the brain must adapt to the unique brain environment and are highly dependent on acetate metabolism for growth and survival. However, the signaling pathways that regulate survival in breast cancer brain metastatic (BCBM) tumors are not known. Primary brain tumor cells can convert acetate to acetyl-CoA via phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by the cyclin-dependent kinase-5 (CDK5) regulated by the nutrient sensor O-GlcNAc transferase (OGT). Here, we show that breast cancer cells selected to metastasize to the brain contain increased levels of O-GlcNAc, OGT and ACSS2-Ser267 phosphorylation compared to parental breast cancer cells. Moreover, OGT and CDK5 are required for breast cancer cell growth in the brain parenchyma in vivo. Importantly, ACSS2 and ACSS2-S267D phospho-mimetic mutant are critical for in vivo breast cancer growth in the brain but not in the mammary fat pad. Mechanistically, we show that ACSS2 regulates BCBM cell survival by suppressing ferroptosis via regulation of E2F1-mediated expression of anti-ferroptotic proteins SLC7A11 and GPX4. Lastly, we show treatment with a novel brain-permeable small molecule ACSS2 inhibitor induced ferroptosis and reduced BCBM growth ex vivo and in vivo. These results suggest a crucial role for ACSS2 in protecting from ferroptosis in breast cancer brain metastatic cells and suggests that breast cancer brain metastatic cells may be susceptible to ferroptotic inducers.

cancer biology↗

bioRxiv2023

Towards a species-level phylogeny for Neotropical Myrtaceae: notes on topology and resources for future studies

Premise of the studyIncreasingly complete phylogenies underpin studies in systematics, ecology, and evolution. Myrteae (Myrtaceae), with c. 2,500 species, is a key component of the exceptionally diverse Neotropical flora, but given its complicated taxonomy, automated assembling of molecular supermatrices from public databases often lead to unreliable topologies due to poor species identification. MethodsHere, we build a taxonomically verified molecular supermatrix of Neotropical Myrteae by assembling 3,954 published and 959 unpublished sequences from two nuclear and seven plastidial molecular markers. We infer a time calibrated phylogenetic tree that covers 712 species of Myrteae (c. 28% of the total diversity in the clade) and evaluate geographic and taxonomic gaps in sampling. Key resultsThe tree inferred from the fully concatenated matrix mostly reflects the topology of the plastid dataset and there is a moderate to strong incongruence between trees inferred from nuclear and plastid partitions. Large, species-rich genera are still the poorest sampled within the group. Eastern South America is the best-represented area in proportion to its species diversity, while Western Amazon, Mesoamerica, and the Caribbean are the least represented. ConclusionsWe provide a time-calibrated tree that can be more reliably used to address finer-scale eco-evolutionary questions that involve this group in the Neotropics. Gaps to be filled by future studies include improving representation of taxa and areas that remain poorly sampled, investigating causes of conflict between nuclear and plastidial partitions and the role of hybridization and incomplete lineage sorting in relationships that are poorly supported.

plant biology↗

bioRxiv2023

More than a prickly morphology: plastome variation in the prickly pear cacti (Opuntieae)

Plastid genomes (plastomes) have long been recognized as highly conserved in their overall structure, size, gene arrangement and content among land plants. However, recent studies have shown that some lineages present unusual variations in some of these features. Members of the cactus family are one of these lineages, with distinct plastome structures reported across disparate lineages including gene losses, inversions, boundary movements, or loss of the canonical inverted repeat (IR) region. Here, we further investigated plastome features of the tribe Opuntieae, the remarkable prickly pear cacti, which represent a diverse and important lineage of Cactaceae. We assembled the plastome of 43 species, representing a comprehensive sampling of the tribe including all seven genera. Plastomes varied considerably in length from 121 kbp to 162 kbp, with striking differences in the content and size of the IR region (contraction and expansion events), including the lack of the canonical IR in some lineages, and the pseudogenization or loss of some genes. Overall, nine different types of plastomes were reported deviating in the presence of the IR region or the genes contained in the IR. Plastomes sequences resolved phylogenetic relationships within major clades of Opuntieae but presented some contentious nodes depending on the data set analyzed (e.g., whole plastome vs. genes only). Incongruence analyses revealed that few plastome regions are supporting the most likely topology, while disputing topologies are driven by a handful of plastome markers, which may be the result of hard recalcitrant nodes in the phylogeny or by the lack of phylogenetic signal in certain markers. Our study reveals a dynamic nature of plastome evolution across closely related lineages, shedding light on peculiar features of cactus plastomes. Variation of plastome types across Opuntieae is remarkable in size, structure, and content, and can be important for the recognition of species in some major clades. Unraveling connections between the causes of plastome variation and the consequences on species biology, ecology, diversification, and adaptation, is a promising endeavor.

plant biology↗

bioRxiv2020

Insights into chloroplast genome variation across Opuntioideae (Cactaceae)

Chloroplast genomes (plastomes) are frequently treated as highly conserved among land plants. However, many lineages of vascular plants have experienced extensive structural rearrangements, including inversions and modifications to the size and content of genes. Cacti are one of these lineages, containing the smallest plastome known for an obligately photosynthetic angiosperm, including the loss of one copy of the inverted repeat ([~]25 kb) and the ndh genes suite, but only a few cacti from the subfamily Cactoideae have been sufficiently characterized. Here, we investigated the variation of plastome sequences across the second-major lineage of the Cactaceae, the subfamily Opuntioideae, to address 1) how variable is the content and arrangement of chloroplast genome sequences across the subfamily, and 2) how phylogenetically informative are the plastome sequences for resolving major relationships among the clades of Opuntioideae. Our de novo assembly of the Opuntia quimilo plastome recovered an organelle of 150,347 bp in length with both copies of the inverted repeats and the presence of all the ndh genes suite. An expansion of the large single copy unit and a reduction of the small single copy was observed, including translocations and inversion of genes as well as the putative pseudogenization of numerous loci. Comparative analyses among all clades within Opuntioideae suggested that plastome structure and content vary across taxa of this subfamily, with putative independent losses of the ndh gene suite and pseudogenization of genes across disparate lineages, further demonstrating the dynamic nature of plastomes in Cactaceae. Our plastome dataset was robust in determining relationships among major clades and subclades within Opuntioideae, resolving three tribes with high support: Cylindropuntieae, Tephrocacteae and Opuntieae. A plastome-wide survey for highly informative phylogenetic markers revealed previously unused regions for future use in Sanger-based studies, presenting a valuable dataset with primers designed for continued evolutionary studies across Cactaceae. These results bring new insights into the evolution of plastomes in cacti, suggesting that further analyses should be carried out to address how ecological drivers, physiological constraints and morphological traits of cacti may be related with the common rearrangements in plastomes that have been reported across the family.

evolutionary biology↗