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 programs. Here we assess 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 demonstrate that several elements act as transcriptional enhancers of important placental genes, such as CSF1R and PSG5. We also identify an LTR10A element that regulates ENG expression, affecting secretion of soluble endoglin, 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.

3D model of harlequin ichthyosis reveals inflammatory therapeutic targets.

The biology of harlequin ichthyosis (HI), a devastating skin disorder caused by loss-of-function mutations in the gene ABCA12, is poorly understood, and to date, no satisfactory treatment has been developed. We sought to investigate pathomechanisms of HI that could lead to the identification of new treatments for improving patients' quality of life. In this study, RNA-Seq and functional assays were performed to define the effects of loss of ABCA12 using HI patient skin samples and an engineered CRISPR/Cas9 ABCA12 KO cell line. The HI living skin equivalent (3D model) recapitulated the HI skin phenotype. The cytokines IL-36α and IL-36γ were upregulated in HI skin, whereas the innate immune inhibitor IL-37 was strongly downregulated. We also identified STAT1 and its downstream target inducible nitric oxide synthase (NOS2) as being upregulated in the in vitro HI 3D model and HI patient skin samples. Inhibition of NOS2 using the inhibitor 1400W or the JAK inhibitor tofacitinib dramatically improved the in vitro HI phenotype by restoring the lipid barrier in the HI 3D model. Our study has identified dysregulated pathways in HI skin that are feasible therapeutic targets.

The Effect of pH on the Extracellular Matrix and Biofilms.

Significance: Chronic wounds become caught in a state of inflammation causing an increase in levels of degrading proteases, which destroy components of the extracellular matrix (ECM) that are essential for the wound healing process. This review aims to highlight and provide readers with an overview of what is currently known about the role of pH and its effect on the ECM and biofilms within healing and nonhealing wounds. Recent Advances: The pH profiles of healthy skin, acute wounds, and chronic wounds differ significantly. Chronic wounds have an alkaline pH whereas healthy skin has a slightly acidic pH. Although there is evidence on the effect of pH on protease production and bacterial proliferation in wounds, there is little evidence to show its effect on ECM synthesis and degradation. Critical Issues: The implications for the complex nature of chronic wounds are that no single treatment is relevant for all wounds, but rather a combination of methodologies must be adopted. It is known that pH of a wound reduces throughout the stages of healing, suggesting that wound pH measurements could be beneficial to identify nonhealing wounds earlier and decide on the most appropriate course of treatment. Future Direction: Wound healing is a very complex process with multiple factors known to play a role. All aspects of the nonhealing wound (defective ECM, pH, microbial invasion, and excess proteases) need to be taken into account when investigating or clinically treating a chronic wound.