TGF-β in progression of liver disease

Transforming growth factor-β (TGF-β) is a central regulator in chronic liver disease contributing to all stages of disease progression from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma. Liver-damage-induced levels of active TGF-β enhance hepatocyte destruction and mediate hepatic stellate cell and fibroblast activation resulting in a wound-healing response, including myofibroblast generation and extracellular matrix deposition. Being recognised as a major profibrogenic cytokine, the targeting of the TGF-β signalling pathway has been explored with respect to the inhibition of liver disease progression. Whereas interference with TGF-β signalling in various short-term animal models has provided promising results, liver disease progression in humans is a process of decades with different phases in which TGF-β or its targeting might have both beneficial and adverse outcomes. Based on recent literature, we summarise the cell-type-directed double-edged role of TGF-β in various liver disease stages. We emphasise that, in order to achieve therapeutic effects, we need to target TGF-β signalling in the right cell type at the right time

Polycystic kidney diseases: From molecular discoveries to targeted therapeutic strategies

Polycystic kidney diseases (PKDs) represent a large group of progressive renal disorders characterized by the development of renal cysts leading to end-stage renal disease. Enormous strides have been made in understanding the pathogenesis of PKDs and the development of new therapies. Studies of autosomal dominant and recessive polycystic kidney diseases converge on molecular mechanisms of cystogenesis, including ciliary abnormalities and intracellular calcium dysregulation, ultimately leading to increased proliferation, apoptosis and dedifferentiation. Here we review the pathobiology of PKD, highlighting recent progress in elucidating common molecular pathways of cystogenesis. We discuss available models and challenges for therapeutic discovery as well as summarize the results from preclinical experimental treatments targeting key disease-specific pathways

Transfer of anthracnose resistance and pod coiling traits from Medicago arborea to M. sativa by sexual reproduction

Five asymmetric hybrid plants were obtained between Medicago sativa (2n = 4x = 32) and Medicago arborea (2n = 4x = 32) through sexual reproduction and the use of a cytoplasmically male sterile M. sativa genotype. Over 2,000 pollinations were made to obtain these hybrids. Amplified fragment length polymorphism (AFLP) analysis showed that in the most studied hybrid (WA2273), 4% of the bands unique to the M. arborea parent were present, versus 72% for the unique M. sativa bands. This suggests that only a single M. arborea chromosome or chromosome parts has been transferred. WA2273 had 7% of AFLP bands which were not present in either parent, which is suggestive of chromosome rearrangements as would be expected if only chromosome parts or a single part had been transferred from M. arborea. Phenotypic evidence for hybridity was obtained for pod coiling (1.4 coils in WA2273 versus three coils in the M. sativa parent and its self and testcross populations, and one coil in M. arborea), and Colletotrichum trifolii race 2 resistance (transferred from the resistant M. arborea parent, as the M. sativa parent and the self populations were highly susceptible). The hybrids were self sterile, but were female fertile to a high level when crossed with 4x, but not 2x, M. sativa, indicating they were at or near 4x. Both the pod coiling trait and anthracnose resistance segregated in the progeny of testcrosses between WA2273 and M. sativa. The work demonstrates that agronomically useful traits can be introgressed into M. sativa from M. arborea by use of male sterile M. sativa and sexual reproduction

Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition

Epithelial to mesenchymal transition (EMT) is an extreme example of cell plasticity, important for normal development, injury repair, and malignant progression. Widespread epigenetic reprogramming occurs during stem cell differentiation and malignant transformation, but EMT-related epigenetic reprogramming is poorly understood. Here we investigated epigenetic modifications during TGF-β-mediated EMT. While DNA methylation was unchanged during EMT, we found global reduction of the heterochromatin mark H3-lys9 dimethylation (H3K9Me2), increase of the euchromatin mark H3-lys4 trimethylation (H3K4Me3), and increase of the transcriptional mark H3-lys36 trimethylation (H3K36Me3). These changes were largely dependent on lysine-specific deaminase-1 (Lsd1), and Lsd1 loss-of-function experiments showed marked effects on EMT-driven cell migration and chemoresistance. Genome-scale mapping revealed that chromatin changes were largely specific to large organized heterochromatin K9-modifications (LOCKs), suggesting that EMT is characterized by reprogramming of specific chromatin domains across the genome