Caley, M. P. | bioRxiv Science

bioRxiv2023

Loss of cholesterol in Junctional Epidermolysis Bullosa skin identifies a key role for Laminin-332 in actomyosin mediated cholesterol transport

Individuals with Junctional Epidermolysis Bullosa (JEB), a rare genetic skin disease characterised by loss of function mutations in the Laminin332 (Lam332), do not survive beyond their first birthday. Here we report that loss of Lam332 leads to absence of cholesterol lipid from the epidermis in vitro and in vivo. Using 3D skin equivalents, a JEB mouse model and JEB patient samples we confirmed changes in epidermal lipid synthesis, which was further explored using lipidomics. Cholesterol biosynthesis genes were increased with loss of Laminin-332 in vitro, however a decrease in immunofluorescence lipid staining was observed. Cholesterol transport in Laminin-332 knockdown keratinocytes was revealed to be disrupted, which in keratinocytes is dependent on the actomyosin network. In conclusion these findings suggest a role for the basement membrane protein Laminin-332 in lipid metabolism in the skin, and a broader role for epidermal homeostasis and barrier formation. Restoration of cholesterol transport in epidermal keratinocytes of JEB patients offers the potential to improve their skin barrier.

cell biology↗

bioRxiv2022

Regulation of human trophoblast gene expression by endogenous retroviruses

The placenta is a fast-evolving organ with large morphological and histological differences across eutherians, but the genetic changes driving placental evolution have not been fully elucidated. Transposable elements, through their capacity to quickly generate genetic variation and affect host gene regulation, may have helped to define species-specific trophoblast gene expression programmes. Here, we assessed the contribution of transposable elements to human trophoblast gene expression as enhancers or promoters. Using epigenomic data from primary human trophoblast and trophoblast stem cell lines, we identified multiple endogenous retrovirus families with regulatory potential that lie close to genes with preferential expression in trophoblast. These largely primate-specific elements are associated with inter-species gene expression differences, and are bound by transcription factors with key roles in placental development. Using genetic editing we demonstrated that several elements act as transcriptional enhancers of important placental genes, such as CSF1R and PSG5. We also identified an LTR10A element that regulates ENG expression, affecting secretion of soluble ENG, with potential implications for preeclampsia. Our data show that transposons have made important contributions to human trophoblast gene regulation, and suggest that their activity may affect pregnancy outcomes.

genetics↗