Biology subjects

Toohill, K.

Publications and source records attributed to Toohill, K..

2 recordsLinked to original sources

bioRxiv2026

An Intronic SINE at Pou5f1 Links Hormone Signaling to Blastocyst Hatching

Before implantation, mammalian embryos must escape from the zona pellucida, a protective glycoprotein coat that surrounds the blastocyst. This process, known as hatching, is essential for uterine attachment and has been viewed largely as a mechanical consequence of blastocyst expansion and zona weakening. Whether hatching is actively timed by embryo-intrinsic gene regulation remains unclear. Here we show that timely hatching of mouse embryos requires signal-responsive repression of Pou5f1/OCT4 in the trophectoderm by a single intronic B2 short interspersed nuclear element. Deleting this element preserves blastocyst formation and stem-cell competence, but disrupts trophectodermal OCT4 repression, delays zona escape, causes hatching-uterine receptivity mismatch, perturbs implantation-site organization and reduces peri-implantation fitness. CRISPR activation screening, siRNA and pharmacological perturbation, and defined progesterone/estradiol/EGF culture conditions identify an ESRRA-linked endocrine/growth-factor response that requires the B2 element to consolidate trophectoderm maturation. Comparative analyses further show that young intronic SINEs are enriched in developmental gene programs, whereas human POU5F1 intronic Alu elements exhibit genetic constraint and repressive potential. These findings identify intronic SINEs as molecular entry points that couple extracellular cues to lineage-restricted transcriptional control and morphogenic transition.

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↗