Biology subjects

Skavicusa, S.

Publications and source records attributed to Skavicusa, S..

3 recordsLinked to original sources

bioRxiv2025

Species-specific chromatin architecture and neurogenesis mediated by a human enhancer

Genomic modifications underlie the evolution of human features, including a larger neocortex and enhanced cognition. Human Accelerated Regions (HARs) are highly-conserved loci containing human-specific variants and can act as neurodevelopmental enhancers. However, the neurodevelopmental functions of HARs and their mechanism of gene regulation are largely unknown. Here, we show that human (Hs) HAR1984 promotes neurogenesis by influencing species-specific transcription and chromatin interactions. Hs-HAR1984 knock-in chimpanzee (Pt) cortical organoids contain more progenitors and neurons, whereas Pt-HAR1984 knock-in human cortical organoids exhibit the opposite phenotype. Hs-HAR1984 knock-in mice recapitulate increased neurogenesis, producing a thicker cortex with folding. Hi-C reveals HAR1984 exhibits chromatin looping with its target genes ETV5 and TRA2B in human fetal brains, notably reduced in chimpanzee, macaque and mouse neural cells. We show that human-specific mutations in HAR1984 directly promote these interactions, favored by nearby structural variants. Further, we discover that human-specific ETV5 binding auto-regulates enhancer activity. This work demonstrates new molecular mechanisms underlying human-specific neurodevelopment, linking HARs to chromatin architecture, cortical cell fate and expansion and folding of brains.

developmental biology↗

bioRxiv2024

Interferon Epsilon Protects Epithelial Barriers from Viral Infection through Autocrine Intracellular Signaling

Antiviral defenses at mucosal barriers are essential for preventing viral entry and systemic infection. Interferon epsilon (IFN{varepsilon}) is a unique type I IFN that, unlike other family members, is not induced by infection but is constitutively expressed in epithelial tissues. IFN{varepsilon} was initially characterized in the female reproductive tract (FRT), where it provides broad antiviral protection, but its roles outside the FRT remain poorly defined. Here, we used Ifn{varepsilon}-/- mice and single-cell RNA sequencing to delineate IFN{varepsilon} function across distinct mucosal surfaces. In the FRT, Ifn{varepsilon} expression was restricted to specific epithelial subsets, was independent of estrous stage, and maintained basal ISG expression. IFN{varepsilon} was also retained intracellularly in primary human FRT-derived cells. Extending these analyses to the intestine, we found that IFN{varepsilon} is highly expressed in villous-tip enterocytes of the small intestine in vivo, where it sustains inflammatory enterocyte subsets and maintains type III IFN expression. Loss of Ifn{varepsilon} depleted these subsets and rendered mice more susceptible to enteric viral infection. Together, these findings establish IFN{varepsilon} as a constitutively expressed, spatially restricted IFN that coordinates mucosal antiviral defenses across both reproductive and gastrointestinal epithelial tissues.

immunology↗

bioRxiv2024

The Shigella flexneri effector IpaH1.4 facilitates RNF213 degradation and protects cytosolic bacteria against interferon-induced ubiquitylation

A central signal that marshals host defense against many infections is the lymphocyte-derived cytokine interferon-gamma (IFN{gamma}). The IFN{gamma} receptor is expressed on most human cells, and its activation leads to the expression of antimicrobial proteins that execute diverse cell-autonomous immune programs. One such immune program consists of the sequential detection, ubiquitylation, and destruction of intracellular pathogens. Recently, the IFN{gamma}-inducible ubiquitin E3 ligase RNF213 was identified as a pivotal mediator of such a defense axis. RNF213 provides host protection against viral, bacterial, and protozoan pathogens. To establish infections, potentially susceptible intracellular pathogens must have evolved mechanisms that subdue RNF213-controlled cell-autonomous immunity. In support of this hypothesis, we demonstrate here that a causative agent of bacillary dysentery, Shigella flexneri, uses the type III secretion system (T3SS) effector IpaH1.4 to induce the degradation of RNF213. S. flexneri mutants lacking IpaH1.4 expression are bound and ubiquitylated by RNF213 in the cytosol of IFN{gamma}-primed host cells. Linear (M1-) and lysine-linked ubiquitylation of S. flexneri requires RNF213 but is independent of the linear ubiquitin chain assembly complex (LUBAC). We find that ubiquitylation of S. flexneri is insufficient to kill intracellular bacteria, suggesting that S. flexneri employs additional virulence factors to escape from host defenses that operate downstream from RNF213-driven ubiquitylation. In brief, this study identified the bacterial IpaH1.4 protein as an inhibitor of mammalian RNF213 and highlights evasion of RNF213-driven immunity as a characteristic of the human-tropic pathogen Shigella.

microbiology↗