Genetic variants associated to type 2 diabetes can modulate endocrine enhancers in vivo

Several genome-wide association studies have shown a clear association between single nucleotide polymorphisms (SNPs) and type 2 diabetes, being the vast majority of these variants located in putative endocrine pancreatic enhancers. This suggests that these SNPs may modulate the enhancer activity and, consequently, gene expression. However, the correlation between SNPs and enhancer activity impairment and the in vivo validation are still poorly explored. Here, by using an in vivo mosaic transgenesis assays in zebrafish, Eufrásio and coworkers from Bessa’s lab at I3S, were able to identify 6 endocrine pancreatic enhancers. The risk variant of two sequences decreased enhancer activity, while in another two incremented it. One of the latter, located in a SLC30A8 exon, results in an aminoacid substitution, being the canonical explanation for the risk of type 2 diabetes the decrease of SLC30A8 function. However, there are other studies that show other type 2 diabetes-associated SNPs that truncate SLC30A8 that can confer protection from this disease. The authors clarified this incongruence by showing that the SLC30A8 gain of function, mediated by the presence of one type 2 diabetes-associated SNP, is the explanation for the increased risk for the disease. To know how, read the full work in Diabetes, in the article entitled In vivo reporter assays uncover changes in enhancer activity caused by type 2 diabetes-associated single nucleotide polymorphisms”.

A conserved notochord enhancer controls pancreas development in Vertebrates

The notochord is an evolutionary novelty in vertebrates that functions as an important signaling center during development. Notochord ablation in chicken has demonstrated that it is crucial for pancreas development. Here, João Amorim, Ana Gali-Macedo and collaborators from José Bessa’s team at I3S show that in zebrafish, the loss of function of Nog2, a Bmp antagonist expressed in the notochord, impairs beta-cell differentiation, compatible with the antagonistic role of Bmp in this process. In addition, the study shows that Nog2 expression in the notochord is induced by at least one notochord enhancer and its loss of function reduces the number of pancreatic progenitors and impairs beta-cell differentiation. Tracing Nog2 diffusion, it was observed that Nog2 emanates from the notochord to the pancreatic progenitor domain. Finally, a notochord enhancer was found in human and mice Nog genomic landscapes, suggesting that the acquisition of a Nog notochord enhancer occurred early in the vertebrate phylogeny and contributes to the development of complex organs like the pancreas.

The article, entitled "A conserved notochord enhancer controls pancreas development in Vertebrates " was published in Cell Reports.

Axial progenitors and the trunk-to-tail transition

During the trunk-to-tail transition, axial progenitors relocate from the epiblast to the tail bud. Rita Aires and collaborators, lead by Moises Mallo from the IGC, show that this process entails a major regulatory switch, bringing tail bud progenitors under Gdf11 signaling control. After Gdf11-induced transition from trunk to tail development, Lin28 genes promote axial progenitor expansion until activation of Hox13 genes overrides this activity. Their work demonstrates that different gene networks regulate axial progenitors at the trunk versus tail levels. More information here.

The article entitled “Tail bud progenitor activity relies on a network comprising Gdf11, Lin28, and Hox13 genes” was published in Developmental Cell.





Fast screening platform for cancer therapy


Despite promising preclinical results, average response rates to anti-VEGF therapies, such as bevacizumab, are reduced for most cancers, while incurring in remarkable costs and side effects. Currently, there are no biomarkers available to select patients that can benefit from this therapy. Depending on the individual tumor, anti-VEGF therapies can either block or promote metastasis. In this context, an assay able to predict individual responses prior to treatment, including the impact on metastasis would prove of great value to guide treatment options. A team from the Champalimaud Foundation led by Rita Fior showed that zebrafish xenografts are able to reveal different responses to bevacizumab in just 4 days, evaluating not only individual tumor responses but also the impact on angiogenesis and micrometastasis. Importantly, the author perform proof-of-concept experiments where clinical responses in patients were compared with their matching zebrafish Patient-Derived Xenografts - zAvatars, opening the possibility of using the zebrafish model to screen bevacizumab therapy in a personalized manner.

The article entitled “Zebrafish xenografts as a fast screening platform for bevacizumab cancer therapy” was published in Communications Biology.

Occluding junctions and epithelial wound repair

In epithelial tissues, cells tightly connect to each other through cell–cell junctions, but they also present the remarkable capacity of reorganizing themselves without compromising tissue integrity. Upon injury, simple epithelia efficiently resolve small lesions through the action of actin cytoskeleton contractile structures at the wound edge and cellular rearrangements. However, the underlying mechanisms and how they cooperate are still poorly understood. By using live imaging of wound repair in the fly Drosophila melanogaster and theoretical modeling Carvalho and collaborators reveal a novel and indispensable role for occluding junctions (OJs) in this process. They demonstrate that OJ loss of function leads to severe defects in wound-closure dynamics: instead of contracting, wounds dramatically increase their area. OJ mutants exhibit phenotypes in cell shape, cellular rearrangements, and mechanical properties as well as in actin cytoskeleton dynamics at the wound edge. The authors propose that OJs are required for wound closure by impacting on tissue mechanical properties, which in turn is crucial for the correct regulation of the cellular events occurring at the wound edge.

The article entitled “Occluding junctions as novel regulators of tissue mechanics during wound repair”was published in The Journal of Cell Biology.