Biology subjects

Hsu, E.

Publications and source records attributed to Hsu, E..

7 recordsLinked to original sources

bioRxiv2026

Identification of Heterogeneous Cortical Thickness Patterns Associated with Prenatal Gestational Diabetes Exposure: A SuStaIn-Based Subtyping Study

ImportancePrenatal exposure to gestational diabetes mellitus (GDM) has been associated with adverse metabolic, neurodevelopmental, and psychiatric outcomes in offspring. However, whether GDM-exposed youth exhibit heterogeneous neuroanatomical patterns remains unclear. ObjectiveTo identify distinct cortical thickness subtypes among GDM-exposed youth and examine their associations with anthropometric, neurocognitive, psychiatric/behavioral and neuroimaging measures both cross-sectionally and longitudinally. Design, Setting, and ParticipantsThis cohort study used the Adolescent Brain Cognitive Development (ABCD)(R)data, a multisite longitudinal population study. Subtype and Stage Inference (SuStaIn), an unsupervised machine learning framework, was applied to cross-sectional structural MRI data to identify cortical thickness patterns in 573 GDM-exposed youth and 2854 healthy controls. Posthoc longitudinal analyses included 1,853 observations from a subset of GDM-exposed youth with 1-, 2-, and 4-year follow-up visits to examine subtype differences in developmental trajectories over time. Exposure(s)Prenatal exposure to GDM. Main Outcome(s) and Measure(s)The primary outcomes included identification of cortical thickness subtypes and their inferred regional ordering patterns. Secondary outcomes included subtype-specific anthropometric, neurocognitive, psychiatric/behavioral and neuroimaging measures. ResultsThe GDM-exposed sample had a mean age of 119.02 {+/-} 7.34 months and was 47.5% female. Two cortical thickness subtypes were identified. Between subtypes, Subtype 1 (63.2%) was characterized by earlier inferred insula involvement and was associated with greater height (d = 0.36, pFDR < 0.001) and weight (d = 0.26, pFDR = 0.007), whereas Subtype 2 exhibited earlier inferred frontal involvement and nominally higher Attention-Deficit/Hyperactivity Disorder (ADHD) prevalence (d = 0.08, p = 0.036), steeper longitudinal cortical thinning across all six cortical regions of interest ({beta} range: -0.05 to -0.13, all pFDR < 0.05), and a smaller decline in Obsessive-Compulsive Disorder (OCD) prevalence over time ({beta} = -1.02, pFDR = 0.049). Conclusions and RelevanceGDM exposure was associated with two distinct offspring cortical thickness subtypes, each showing different inferred regional ordering patterns and clinical associations. One subtype showed an insula-cingulate-predominant pattern associated with anthropometric measures, whereas the other showed a frontal-predominant pattern associated with nominally higher psychiatric measures and faster cortical thinning over time.

neuroscience↗

bioRxiv2026

Environmental Regulation and Gene-by-Environment Interaction Influence RAP1 Activity and its Impact on Gene Expression

Gene-by-environment (GxE) interactions play a major role in shaping both phenotypic and molecular variation, with important implications for human health and disease. In this study, we used the Doxycycline (Dox) regulated, tetracycline-responsive (Tet-Off) promoter system to sequentially reduce or titrate gene expression levels of the essential yeast transcription factor Repressor Activator Protein 1 (RAP1) similar to a hypomorph allele series, across three distinct environments: Yeast Peptone Dextrose (YPD) media, YPD media with Heat Shock (HS), and Yeast Peptone Acetate (YPAC) media. We then performed RNA sequencing (RNA Seq) to assess global transcriptional responses to RAP1 reduction in these different growth environments. Our analysis first focused on the independent effects of varying RAP1 expression levels within and across environments. We then explored GxE interactions, revealing a subset of genes with significant consequences of reduced levels of RAP1 and environment-specific expression patterns. Notably, many genes exhibited opposite effects of RAP1 titration on gene expression when yeast were grown in YPAC media compared to YPD media and/or HS, suggesting environment-dependent regulatory architecture. This design reveals how cells integrate internal transcriptional and regulatory changes with external environmental cues, providing a deeper view of GxE architecture. Using Weighted Gene Co-expression Network Analysis (WGCNA), we identified co-regulated gene modules, and by combining this with transcription factor motif enrichment tests, our study identified candidate regulators driving their dynamics. Our findings demonstrate that gene regulatory networks can vary dramatically depending on the environmental context an organism experiences, which can then influence the specific phenotypes produced by a particular genetic perturbation. This illustrates the complexity of genotype-environment interactions and the importance of studying gene function in multiple environments to gain a truly comprehensive understanding of a genes sometimes numerous and diverse functions.

genomics↗

bioRxiv2025

Persistent Activation of Endothelial Cells is Linked to Thrombosis and Inflammation in Cerebral Cavernous Malformation Disease

AbstractO_ST_ABSBACKGROUNDC_ST_ABSCerebral cavernous malformations (CCM) are neurovascular lesions that affect both children and adults, and morbidity often results from thrombosis, bleeding, and neurological dysfunction. Studies indicate that inflammation-related activation of endothelial cells contributes significantly to the worsening of CCM disease. This suggests that ongoing vascular inflammation and endothelial dysfunction are key factors associated with thrombosis and bleeding in CCM disease. However, the inflammatory mechanisms leading to altered brain endothelial cell function with a high propensity for thrombosis, inflammation, and dysfunction are not fully understood. METHODSMulti-omic analyses was conducted by performing simultaneous high-throughput single-nucleus RNA sequencing (snRNA-seq) and single-nucleus transposase-accessible chromatin sequencing (snATAC-seq) with the 10x Genomics multiome platform in combination with immunofluorescence to study CCM pathogenesis in both female and male mice with CCM (Slco1c1-CreERT2; Pdcd10fl/fl) disease. The analysis was complemented with bulk RNA-seq, bulk ATAC-seq, and ChIP-seq (Chromatin immunoprecipitation sequencing) using an in vitro human CCM model. An AAV-BR1 viral system selectively upregulates the activator protein-1 (AP-1) transcription factor JUNB in brain endothelial cells was used to evaluate its effectiveness in maintaining a persistent activated cell state during the pathogenesis of CCM. RESULTSWe found that epigenetics significantly influences the subtype identity and function of brain endothelial cells within the arteriovenous axis. Through multi-omic analyses, specific regulatory elements and enhancers (cis-Regulatory Elements, cCREs) in mouse brain endothelial cells were identified that influence subtype-specific transcriptional programs and the transcription factors responsible for establishing the various subtypes of brain endothelial cells. Additionally, large-scale epigenomic reprogramming of brain endothelial cell subtypes was observed during the pathogenesis of CCM disease. Among the most significant changes were alterations in the chromatin state of endothelial cells, along with transcriptional processes associated with a persistently activated endothelial cell state, which renders them susceptible to inflammation and thrombosis. The activator AP-1 transcription factor JUNB was identified as a key regulator of the persistently activated endothelial state during chronic neuroinflammation. Moreover, both trans- and cis-regulatory factors conserved between mice and humans were discovered and contribute to the progression of chronic CCM disease. CONCLUSIONSEpigenetics plays a crucial role in determining the transcription patterns and functions of brain arteriovenous endothelial cells. The activator JUNB is identified as a driver of chronic brain vascular inflammation by inducing a persistent activated endothelial cell state from epigenome reprogramming. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/662238v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1297edforg.highwire.dtl.DTLVardef@1488e27org.highwire.dtl.DTLVardef@6cae62org.highwire.dtl.DTLVardef@12cb282_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2023

Multicore fiber optic imaging reveals that astrocyte calcium activity in the cerebral cortex is modulated by internal motivational state

Astrocytes are a direct target of neuromodulators and can influence neuronal activity on broad spatial and temporal scales through their close proximity to synapses. However, our knowledge about how astrocytes are functionally recruited during different animal behaviors and their diverse effects on the CNS remains limited. To enable measurement of astrocyte activity patterns in vivo during normative behaviors, we developed a high-resolution, long working distance, multi-core fiber optic imaging platform that allows visualization of cortical astrocyte calcium transients through a cranial window in freely moving mice. Using this platform, we defined the spatiotemporal dynamics of astrocytes during diverse behaviors, ranging from circadian fluctuations to novelty exploration, showing that astrocyte activity patterns are more variable and less synchronous than apparent in head-immobilized imaging conditions. Although the activity of astrocytes in visual cortex was highly synchronized during quiescence to arousal transitions, individual astrocytes often exhibited distinct thresholds and activity patterns during explorative behaviors, in accordance with their molecular diversity, allowing temporal sequencing across the astrocyte network. Imaging astrocyte activity during self-initiated behaviors revealed that noradrenergic and cholinergic systems act synergistically to recruit astrocytes during state transitions associated with arousal and attention, which was profoundly modulated by internal state. The distinct activity patterns exhibited by astrocytes in the cerebral cortex may provide a means to vary their neuromodulatory influence in response to different behaviors and internal states.

neuroscience↗

bioRxiv2020

Adenovirus E1A Binding to DCAF10 Targets Degradation of AAA+ ATPases Required for Quaternary Assembly of Multiprotein Machines and Innate Immunity

Adenovirus E1A early proteins modify host cell physiology to optimize virus replication. The N-terminal half of small e1a interacts with RB-family proteins to de-repress dNTP and DNA synthesis, and with p300/CBP to inhibit host anti-viral innate immune responses. These e1a N-terminal interactions activate a strong, late host anti-viral response due to stabilization and activation of interferon response factor 3 (IRF3). However, the C-terminal half of e1a inhibits this through interactions with three host proteins with seemingly unrelated functions. Proteomic analysis showed that all three C-terminal interactions are required for e1a-association into an [~]1 MDa multi-protein complex with scaffold subunits of a CRL4 E3 ubiquitin ligase and DCAF10, a presumed specificity subunit. This e1a-DCAF10-CRL4 prevents IRF3 stabilization indirectly by directing degradation of the essential AAA+ ATPases RUVBL1/2, subunits of several HSP90 co-chaperones required for quaternary assembly of cellular protein machines required for anti-viral defenses and responses to genotoxic and metabolic stress.

microbiology↗

bioRxiv2020

Promoter-specific changes in initiation, elongation and homeostasis of histone H3 acetylation during CBP/p300 Inhibition

Regulation of RNA Polymerase II (Pol2) elongation in the promoter proximal region is an important and ubiquitous control point for gene expression in metazoan cells. We report that transcription of the adenovirus 5 E4 region is regulated during the release of paused Pol2 into productive elongation by recruitment of the super elongation complex (SEC), dependent on promoter H3K18/27 acetylation by CBP/p300. We also establish that this is a general transcriptional regulatory mechanism for [~]6% of genes expressed with FPKM>1 in primary human airway epithelial cells. We observed that a homeostatic mechanism maintains promoter, but not enhancer H3K18/27ac in response to extensive inhibition of CBP/p300 acetyl transferase activity by the highly specific small molecule inhibitor A-485. Further, our results suggest a function for BRD4 association at enhancers in regulating paused Pol2 release at nearby promoters. Taken together, our results uncover processes regulating transcriptional elongation by promoter region histone H3 acetylation and homeostatic maintenance of promoter, but not enhancer, H3K18/27ac in response to inhibition of CBP/p300 acetyl transferase activity.

molecular biology↗

bioRxiv2020

Vanishing white matter disease expression of truncated EIF2B5 activates induced stress response

Vanishing White Matter disease (VWM) is a severe leukodystrophy of the central nervous system caused by mutations in subunits of the eukaryotic initiation factor 2B complex (eIF2B). Current models only partially recapitulate key disease features, and pathophysiology is poorly understood. Through development and validation of zebrafish (Danio rerio) models of VWM, we demonstrate that zebrafish eif2b mutants phenocopy VWM, including impaired somatic growth, early lethality, impaired myelination, loss of oligodendrocyte precursor cells, increased apoptosis in the CNS, and impaired motor swimming behavior. Expression of human EIF2B2 in the zebrafish eif2b2 mutant rescues lethality and CNS apoptosis, demonstrating conservation of function between zebrafish and human. In the mutants, intron 12 retention leads to expression of a truncated eif2b5 transcript. Expression of the truncated eif2b5 in wild-type larva impairs motor behavior and activates the ISR, suggesting that a feed-forward mechanism in VWM is a significant component of disease pathophysiology.

physiology↗