Biology subjects

Cowley, C. J.

Publications and source records attributed to Cowley, C. J..

3 recordsLinked to original sources

bioRxiv2023

Stem cells tightly regulate dead cell clearance to maintain tissue fitness

Summary ParagraphMacrophages and dendritic cells have long been appreciated for their ability to migrate to and engulf dying cells and debris, including some of the billions of cells that are naturally eliminated from our body daily. However, a substantial number of these dying cells are cleared by non-professional phagocytes, local epithelial cells that are critical to organismal fitness. How non-professional phagocytes sense and digest nearby apoptotic corpses while still performing their normal tissue functions is unclear. Here, we explore the molecular mechanisms underlying their multifunctionality. Exploiting the cyclical bouts of tissue regeneration and degeneration during the hair cycle, we show that stem cells can transiently become non-professional phagocytes when confronted with dying cells. Adoption of this phagocytic state requires both local lipids produced by apoptotic corpses to activate RXR, and tissue-specific retinoids for RAR{gamma} activation. This dual factor dependency enables tight regulation of the genes requisite to activate phagocytic apoptotic clearance. The tunable phagocytic program we describe here offers an effective mechanism to offset phagocytic duties against the primary stem cell function of replenishing differentiated cells to preserve tissue integrity during homeostasis. Our findings have broad implications for other non-motile stem or progenitor cells which experience cell death in an immune-privileged niche.

cell biology↗

bioRxiv2022

A tissue injury repair pathway distinct but parallel to host pathogen defense

Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces interferons (IFNs) to activate resistance mechanisms. Applying unbiased phylogenetic analysis, we show that interleukin-24 (IL24) is among the closest evolutionary homologs to the IFN family and shares a common ancestral origin. However, in contrast to IFNs, IL24 induction occurs specifically in barrier epithelial progenitors after injury and is independent of microbiome or adaptive immunity. Surprisingly, Il24 ablation impedes not only epidermal proliferation and re-epithelialization, but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic Il24 induction in homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, sustained Il24 expression depends upon both IL24 receptor/STAT3 signaling and also hypoxia-stabilized HIF1, which converge following injury. Thus, parallel to the IFN-mediated innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL24-mediated tissue repair.

immunology↗

bioRxiv2021

Characterization of sequence determinants of enhancer function using natural genetic variation

Sequence variation in enhancers, a class of cis-regulatory elements that control cell type-specific gene transcription, contributes significantly to phenotypic variation within human populations. Enhancers are short DNA sequences ([~]200 bp) composed of multiple binding sites (4-10 bp) for transcription factors (TFs). The transcriptional regulatory activity of an enhancer is encoded by the type, number, and distribution of TF binding sites that it contains. However, the sequence determinants of TF binding to enhancers and the relationship between TF binding and enhancer activity are complex, and thus it remains difficult to predict the effect of any given sequence variant on enhancer function. Here, we generate allele-specific maps of TF binding and enhancer activity in fibroblasts from a panel of F1 hybrid mice that have a high frequency of sequence variants. We identified thousands of enhancers that exhibit differences in TF binding and/or activity between alleles and use these data to define features of sequence variants that are most likely to impact enhancer function. Our data demonstrate a critical role for AP-1 TFs at many fibroblast enhancers, reveal a hierarchical relationship between AP-1 and TEAD TF binding at enhancers, and delineate the nature of sequence variants that contribute to AP-1 TF binding. These data represent one of the most comprehensive assessments to date of the impact of sequence variation on enhancer function in chromatin, with implications for identifying functional cis-regulatory variation in human populations.

genomics↗