Project description:Ulcerative colitis is a chronic inflammatory disorder for which a definitive cure is still missing. This is characterized by an overwhelming inflammatory milieu in the colonic tract where a composite set of immune and non-immune cells orchestrate its pathogenesis. Over the last years, a growing body of evidence has been pinpointing gut virome dysbiosis as underlying its progression. Nonetheless, its role during the early phases of chronic inflammation is far from being fully defined. Here we show the gut virome-associated Hepatitis B virus protein X, most likely acquired after an event of zoonotic spillover, to be associated with the early stages of ulcerative colitis and to induce colonic inflammation in mice. It acts as a transcriptional regulator in epithelial cells, provoking barrier leakage and altering mucosal immunity at the level of both innate and adaptive immunity. This study paves the way to the comprehension of the aetiopathogenesis of intestinal inflammation and encourages further investigations of the virome as a trigger also in other scenarios. Moreover, it provides a brand-new standpoint that looks at the virome as a target for tailored treatments, blocking the early phases of chronic inflammation and possibly leading to better disease management.
Project description:Bats (order Chiroptera) are the only mammals capable of self-powered flight. Unlike in humans and mice, digits II-V in the bat forelimb are not separated but connected by the chiropatagium, an elastic membrane that forms the wing. The molecular underpinnings of these morphological differences, one of the most striking adaptations in mammalian evolution, remain obscure. Here, we use a suite of omics tools and single-cell analyses to compare the development of fore- and hindlimbs, in bat and mouse. We demonstrate a clear conservation of cell states and processes between species, even at the level of apoptosis, a mechanism that removes the tissue between the digits. To trace down the cellular origin of the persistent interdigital cells in bats, we micro-dissected the embryonic chiropatagium and performed single-cell transcriptomics. We found that the chiropatagium cells develop from fibroblasts populations, and independently from the apoptosis-related retinoic acid signaling cells of the interdigital mesenchyme. These cells from the distal part of the limb repurpose a gene program otherwise only present in proximal cells. Epigenomic and gene network analyses revealed two transcription factors, MEIS2 and TBX3, among the most prominent regulators of this gene program. Transgenic ectopic expression of MEIS2 and TBX3 in interdigital cells of mice resulted in the activation of genes associated with bat wing processes. Major morphological changes in these mutants include an increase in autopod volume, extracellular matrix and the partial retention of interdigital tissue with fusion (syndactyly) of digits. Our results elucidate fundamental molecular mechanisms of wing formation in bats. More generally, we illustrate that the repurposing of existing developmental programs is an evolutionary molecular mechanism to generate morphological novelties.
Project description:Bats (order Chiroptera) are the only mammals capable of self-powered flight. Unlike in humans and mice, digits II-V in the bat forelimb are not separated but connected by the chiropatagium, an elastic membrane that forms the wing. The molecular underpinnings of these morphological differences, one of the most striking adaptations in mammalian evolution, remain obscure. Here, we use a suite of omics tools and single-cell analyses to compare the development of fore- and hindlimbs, in bat and mouse. We demonstrate a clear conservation of cell states and processes between species, even at the level of apoptosis, a mechanism that removes the tissue between the digits. To trace down the cellular origin of the persistent interdigital cells in bats, we micro-dissected the embryonic chiropatagium and performed single-cell transcriptomics. We found that the chiropatagium cells develop from fibroblasts populations, and independently from the apoptosis-related retinoic acid signaling cells of the interdigital mesenchyme. These cells from the distal part of the limb repurpose a gene program otherwise only present in proximal cells. Epigenomic and gene network analyses revealed two transcription factors, MEIS2 and TBX3, among the most prominent regulators of this gene program. Transgenic ectopic expression of MEIS2 and TBX3 in interdigital cells of mice resulted in the activation of genes associated with bat wing processes. Major morphological changes in these mutants include an increase in autopod volume, extracellular matrix and the partial retention of interdigital tissue with fusion (syndactyly) of digits. Our results elucidate fundamental molecular mechanisms of wing formation in bats. More generally, we illustrate that the repurposing of existing developmental programs is an evolutionary molecular mechanism to generate morphological novelties.