Biology subjects

Natua, S.

Publications and source records attributed to Natua, S..

3 recordsLinked to original sources

bioRxiv2026

Inbred and outcrossed Drosophila embryos diverge in stress defense and developmental maintenance during heat stress

Early embryos must mount stress defenses without compromising the developmental programs that drive morphogenesis, but whether genetic background alters this balance remains unclear. We compared cellularizing Drosophila melanogaster embryos from inbred and outcrossed backgrounds under control conditions and after acute or chronic heat-stress. Both backgrounds developed successfully and showed modest transcriptomic differences at 18{degrees}C. Heat stress at 32{degrees}C, however, sharply separated their phenotypic and transcriptional responses. Inbred embryos showed poor larval hatching after acute and chronic heat, and this deficit persisted through adult eclosion. Their transcriptomes exhibited a greater stress-response burden, with enrichment of proteostasis, DNA repair, mitochondrial maintenance, RNA processing, and metabolic remodeling programs. Outcrossed embryos retained substantially greater developmental survival and higher abundance of transcripts associated with development, adhesion, epithelial organization, signaling, transport, sensory responses, and morphogenesis. Background-dependent divergence was greatest during acute heat. Under chronic heat, background-dependent differences were fewer, with most overlapping those seen during acute heat and a smaller set detected only under chronic heat. Transcript-origin analysis further showed that acute outcrossed-biased genes were predominantly maternally derived and showed no enrichment for purely zygotic transcripts, whereas chronic outcrossed-biased genes contained a larger zygotic component. In summary, the less viable inbred background mounted the broader molecular stress signature, whereas the more viable outcrossed background retained greater abundance of development-associated transcripts. These findings identify genetic background as a major determinant of how embryonic heat responses are distributed between molecular stress defense and developmental gene expression.

genetics↗

bioRxiv2025

Reducing Cofilin dosage makes embryos resilient to heat stress

In addition to regulating actin dynamics, Cofilin also senses and responds to physiological stress and can determine cell survival outcomes. Yet, the full picture of Cofilin's role in stress response is lacking. Here, we used imaging and RNA-seq methods to show that exposing early Drosophila melanogaster embryos to either acute or chronic heat stress (32{degrees}C) induces a Cofilin-mediated Actin Stress Response (ASR) and leads to upregulation of genes associated with both heat shock and Endoplasmic Reticulum (ER) unfolded protein responses. Reducing cofilin gene dosage (cofilin+/-) in heat-stressed embryos modulates all observed stress responses and partially rescues embryo survival. Unexpectedly we find that heat shock- and ER- stress response modulation arises because non-stressed cofilin+/- embryos already show upregulation of heat shock- and ER- stress response genes, prior to heat exposure. Our data support a model whereby cofilin heterozygosity activates specific stress responses associated with reduced protein homeostasis, thus priming embryos to be more resilient when they encounter subsequent heat stress. We conclude that Cofilin dosage serves as a determinant of stress outcomes, impacting both the actin cytoskeleton and inducible stress response pathways. In the embryo, we identify Cofilin as a novel link between inducible stress response and thermotolerance.

developmental biology↗

bioRxiv2024

Dysregulated RNA splicing induces regeneration failure in alcohol-associated liver disease

Individuals with progressive liver failure are at a high risk of mortality without liver transplantation. However, our understanding of derailed regenerative responses in failing livers is limited. Here, we performed comprehensive multi-omic profiling of healthy and diseased human livers using bulk and single-nucleus RNA-plus ATAC-seq. We report that hepatic immune milieu alterations in alcohol-associated liver disease (ALD) prevent hepatocytes from transitioning to a proliferative progenitor-like state, trapping them into an unproductive intermediate state. We discovered striking changes in RNA binding protein (RBP) expression, particularly ESRP, PTBP, and SR families, that cause misregulation of developmentally controlled RNA splicing in ALD. Our data pinpoint ESRP2 as a pivotal disease-sensitive RBP and support a causal role of its deficiency in ALD pathogenesis. Notably, splicing defects in ESRP2-targets Tcf4 and Slk, amongst others, directly alter their nuclear localization and activities, disrupting WNT and Hippo signaling pathways, which are critical for normal liver regeneration. We demonstrate that changes in stromal cell populations enrich failing ALD livers with TGF-{beta}, which suppresses ESRP2-driven epithelial splicing program and replaces functional parenchyma with quasi-progenitor-like cells lacking liver-specific functions. This unprecedented account of transcriptional and post-transcriptional dysregulation in ALD suggests that targeting misspliced RNAs could improve recovery and serve as biomarkers for poor ALD outcomes.

molecular biology↗