Biology subjects

Hill, E. J.

Publications and source records attributed to Hill, E. J..

9 recordsLinked to original sources

bioRxiv2026

Globular domain histone H3R131C mutation remodels chromatin accessibility to promote oncogenic transcriptional programs

Histone mutations, characterized as oncohistones, have emerged as important oncogenic driver events by altering chromatin structure and/or chromatin modifications, thereby dysregulating gene expression. While H3 tail domain oncohistone mutations such as H3K27M and H3K36M are well characterized, it is currently unknown whether mutations within the H3 globular domain represent oncogenic driver events. Using publicly available cancer patient tumor data, here we identify H3R131C as a recurrent histone H3 globular domain mutation. H3R131C mutation is present in diverse human tumors including breast and bladder cancers. Phenotypic assays demonstrate that H3R131C expression does not augment cellular proliferation but enhances cellular migration and invasion. H3R131C frequently co-occurs with mutations in oncogenes including PIK3CA and ESR1, and tumor suppressors TP53 and CDKN2A with an allele frequency consistent with H3R131C representing a subclonal event that enhances tumor fitness rather than initiating transformation. Mechanistically, ATAC-seq reveals that H3R131C expression increases chromatin accessibility, with enrichment of AP-1/bZIP transcription factor motifs at gained accessible regions. Integration of chromatin accessibility and transcriptomic profiling identifies concordant upregulation of pro-oncogenic target genes including PGF, SOX5, and CCDC88C, supporting a model in which H3R131C destabilizes the nucleosome to remodel chromatin and activate transcriptional programs associated with cellular migration, angiogenesis, and epithelial plasticity. Collectively, these findings identify H3R131C as a functionally active globular domain oncohistone that reshapes the epigenome to promote oncogenic gene expression.

cancer biology↗

bioRxiv2026

Human spinal cord organoids recapitulate developmental and disease-associated oligodendrocyte lineage signatures

Oligodendrocytes play essential roles in central nervous system development and homeostasis, and their dysfunction is a hallmark of numerous neurological disorders. However, human in vitro systems that support oligodendrocyte lineage progression while enabling the study of disease-relevant states remain limited. Here, we establish human spinal cord organoids (hSpO) and cortico-motor assembloids as platforms to model oligodendrocyte development, neuron-glia interactions, and cytokine-induced dysfunction. We show that hSpO generate oligodendrocyte lineage populations that transcriptionally resemble those found in the developing human spinal cord, and oligodendrocyte progenitor cells that exhibit physiologically-relevant functional properties, including migration and monosynaptic input from neurons. Exposure of assembloids to pro-inflammatory cytokines induces transcriptional changes across the oligodendrocyte lineage, characterized by altered lineage progression and acquisition of disease-associated gene expression programs that mirror signatures observed in multiple sclerosis patient tissue. Together, this work establishes hSpO and assembloids as in vitro systems for studying oligodendrocyte lineage development and disease-associated states in a human multi-cellular context.

cell biology↗

bioRxiv2025

Lead (Pb) exposure alters neural cell fate in the developing human brain

The heavy metal lead (Pb) is a developmental neurotoxicant associated with cognitive and behavioral deficits, but the cellular mechanisms underlying these impairments remain unclear. Here we show that prenatal Pb exposure biases human radial glia fate, prolonging neurogenesis and suppressing astrogenesis. We used hiPSC-derived cortical organoids, primary human fetal tissue, and in vivo xenografts to demonstrate that Pb exposure alters radial glial differentiation. Pb-exposed organoids contain a higher proportion of neurons and fewer astrocytes. We validated this differentiation bias in primary radial glia from human cortices (GW16-20), observing Pb-associated reductions in astrocyte commitment via genetic lineage tracing. This correlated with increased H3K27me3, a repressive histone modification deposited by the histone methyltransferase complex PRC2, suggesting epigenetic reprogramming as a mechanistic link between Pb and neural cell fate commitment. Our findings indicate that prenatal Pb exposure impacts lineage commitment in the developing brain, which may contribute to cognitive and behavioral impairment.

neuroscience↗

bioRxiv2025

Temporal regulation of human reactive astrocytes reveals their capacity for antigen presentation

Astrocytes adapt to injury and disease by entering a reactive state defined by transcriptomic, morphological, and functional changes. Using a combination of human cortical organoids (hCOs) and primary fetal brain tissue, we investigated the plasticity of human astrocyte reactivity. We observed robust inflammatory transcriptomic and chromatin signatures following cytokine exposure, which varied with duration. To assess reversibility, we withdrew cytokines after acute or chronic exposure. In both cases, astrocytes returned to a quiescent genomic state within days. Chronic exposure induced MHC class II gene expression, normally restricted to professional antigen-presenting cells. We validated MHCII protein in primary tissue and hCOs and used co-immunoprecipitation and mass spectrometry to identify candidate antigens. Finally, we showed that exogenous peptides from fetal neurons could be presented by astrocytic MHCII.

neuroscience↗

bioRxiv2024

Astrocytes control UP state and slow oscillation periodicity in human cortical networks

Astrocytes are well known for homeostatic roles in energy maintenance, neurotransmitter recovery and immunoreactivity, however their contributing role in active modulation of neuronal activity remains controversial. Recent evidence highlights astrocytes as a potential signalling partner in ongoing high-order neuronal activity, and a modulator of baseline activity. Here we utilise an iPSC-derived in vitro cortical network model to describe a slow-wave oscillation and examine the contributions of astrocytes to development of this oscillatory activity, dependant upon generation of UP/DOWN state phenomena. To examine the role of astrocytes we invoke an acetylcholinergic oscillation in the neuronal population by addition of carbachol, which proved to be a robust mechanism for eliciting prolonged and synchronised network bursting. Pharmalogical interrogation determined oscillatory maintenance was dependent on both glutamatergic and purinergic signalling pathways. Upon further interrogation, we determined that astrocytic calcium signalling was essential to timing of the oscillatory signal. By utilising chemogenetic actuators we showed that whilst neurons are essential and sufficient for instigating the oscillatory signal, astrocytes played a key role in timing. This previously unreported mechanism may contribute to initial development of brain activity, and may underlie a basal activity present later during adulthood. In collaboration with recent results highlighting the role of active gliotransmission, this highlights astrocytes as an important research target for understanding brain activity alterations during development and disease.

neuroscience↗

bioRxiv2023

Ectopic transcription due to inappropriately inherited histone methylation may interfere with the ongoing function of terminally differentiated cells

How mutations in histone modifying enzymes lead to neurodevelopmental disorders is unknown. We took advantage of the invariant embryonic lineage and adult nervous system in C. elegans to investigate a double mutant between spr-5/Lsd1/Kdm1a (H3K4me1/2 demethylase) and met-2/Setdb1 (H3K9 methyltransferase). We demonstrate that spr-5; met-2 double mutant worms have a severe chemotaxis defect caused by the ectopic expression of germline genes in somatic tissues. Despite this behavioral defect, we observe few embryonic lineage alterations and an intact adult nervous system. This raises the possibility that the abnormal chemotaxis behavior may be due to ongoing defects in terminally differentiated cells rather than alterations in development. Remarkably, we found that shutting off the ectopic germline expression rescues normal chemotaxis in the same spr-5; met-2 adult worms that had a chemotaxis defect earlier. This suggests that ongoing inappropriate transcription can block normal behavior in an intact nervous system. Based on these data, it is possible that the intellectual disability and altered behavior observed in human neurodevelopmental syndromes caused by mutations in histone modifying enzymes could be due to ongoing ectopic transcription and may be reversible.

developmental biology↗

bioRxiv2023

Altered metabolic function induced by amyloid-beta oligomers and PSEN1-mutations in iPSC-derived astrocytes.

Altered energy metabolism in Alzheimers disease (AD) is considered a major pathological hallmark implicated in the early stages of the disease process. Astrocytes play a central role in brain homeostasis and are increasingly implicated in multiple neurodegenerative diseases. We report that astrocytes differentiated from early onset familial Alzheimers disease (fAD) patients or control cells treated with Amyloid {beta} oligomers exhibit significant changes in their metabolism including glucose uptake, glutamate uptake and lactate release, with increases in oxidative and glycolytic metabolism. Furthermore, we demonstrate evidence of gliosis in fAD astrocytes in addition to a change in metabolic pathways including glutamate, purines, arginine, and the citric acid cycle. Homeostatic responses to brain activity and cellular metabolism are central to normal brain function. However, altered brain metabolism and cellular stress present significant risk factors for the onset and progression of neurodegenerative disease. This study demonstrates that fAD derived astrocytes present multiple metabolic and disease associated phenotypes early in their development suggesting that chronic alterations in fAD patient early in life that present significant risk factors for disease progression in mid-life and suggest key targets for potential diagnostic features and therapeutic agents late onset dementia in midlife.

neuroscience↗

bioRxiv2020

Lyve-1 expressing perivascular macrophages orchestrate pericyte expansion to sustain angiogenesis in cancer

Tumor associated macrophages (TAMs) are a highly plastic stromal cell type which support cancer progression. Using single-cell RNA-sequencing of TAMs from a spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT) we characterize a subset of these cells expressing lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve-1) which spatially reside proximal to blood vasculature. We demonstrate that Lyve-1+ TAMs support tumor growth and identify a pivotal role for these cells in maintaining a population of perivascular mesenchymal cells which express alpha-smooth muscle actin and phenotypically resemble pericytes. Using photolabeling techniques show that mesenchymal cells maintain their prevalence in the growing tumor through proliferation and uncover a role for Lyve-1+ TAMs in orchestrating a selective platelet-derived growth factor-CC-dependent expansion of the perivascular mesenchymal population, creating a pro-angiogenic niche. This study highlights the inter-reliance of the immune and non-immune stromal network which support cancer progression and provides therapeutic opportunities for tackling the disease.

cancer biology↗

bioRxiv2018

Genome-wide screens in accelerated human stem cell-derived neural progenitor cells identify Zika virus host factors and drivers of proliferation

Neural progenitor cells (NPCs) are essential to brain development and their dysfunction is linked to several disorders, including autism, Zika Virus Congenital Syndrome, and cancer. Understanding of these conditions has been improved by advancements with stem cell-derived NPC models. However, current differentiation methods require many days or weeks to generate NPCs and show variability in efficacy among cell lines. Here, we describe human Stem cell-derived NGN2-accelerated Progenitor cells (SNaPs), which are produced in only 48 hours. SNaPs express canonical forebrain NPC protein markers, are proliferative, multipotent, and like other human NPCs, are susceptible to Zika-mediated death. We further demonstrate SNaPs are valuable for large-scale investigations of genetic and environmental influencers of neurodevelopment by deploying them for genome-wide CRISPR-Cas9 screens. Our studies expand knowledge of NPCs by identifying known and novel Zika host factors, as well as new regulators of NPC proliferation validated by re-identification of the autism spectrum gene PTEN.

neuroscience↗