Biology subjects

Tai, J.

Publications and source records attributed to Tai, J..

7 recordsLinked to original sources

bioRxiv2026

Paternal regulation of H3K4 methylation supports tumor suppressor networks in mammals intergenerationally

Paternally-inherited epigenetic information can influence phenotype in offspring (1). Here, we identify a critical mechanistic contribution of KDM6A (UTX), an X-linked histone modifier and tumor suppressor, in regulating transmissible epigenetic information in mammalian sperm. Paternal loss of KDM6A increases cancer risk in genetically wild type offspring, but how Kdm6a knockout sperm transmit this effect at the molecular level is unknown (2). We find that KDM6A functions in spermatogenesis to promote methylation of histone H3 lysine 4 (H3K4) via selective interaction with the COMPASS complex methyltransferase KMT2C (MLL3). KMT2C and KDM6A are coordinately recruited to promoters of active genes in spermatogenic cells, contrasting with recruitment to intergenic enhancers in other cell types (3, 4). Loss of KDM6A disrupts H3K4 methylation at promoters of tumor suppressor genes in spermatogonia, and some of these defects persist in epididymal sperm and correspond to impaired expression in preimplantation embryos. These genes are also misregulated in normal and malignant hematopoietic tissue of genetically wild type offspring, indicating that impaired H3K4 methylation in KDM6A-deficient male germ cells may preferentially alter regulation of tumor suppressor gene networks in development across generations.

genetics↗

bioRxiv2026

Paraventricular thalamus gates hippocampal coding of salient experiences.

Adaptive behavior requires neural circuits that encode salient stimuli to guide approach and avoidance. The hippocampal ventral subiculum (vSub) encodes information related to avoidance and reward seeking, yet how upstream inputs shape its representations of salient appetitive and aversive events remains unclear. Here, we show that a projection from the anterior paraventricular thalamus (PVT) to vSub carries an aversive-state signal that biases vSub representations toward threat-related information. In anxiety-provoking environments, anterior PVT to vSub activity is associated with avoidance behavior and enhanced vSub discrimination of threat and safety. During associative learning, this circuit preferentially promotes vSub responses to threat-predictive cues and aversive outcomes while constraining representations of rewarding stimuli. These findings refine canonical limbic circuit models by identifying a direct thalamic influence over hippocampal coding of rewarding versus aversive stimuli and the approach-avoidance behaviors they guide.

neuroscience↗

bioRxiv2026

Ancestral chromatin state constrains the functional landscape of bivalent domains in mammalian spermatogenesis

Mammalian germ cells are enriched for bivalent chromatin, an epigenetic state defined by the dual presence of the activating H3K4me3 and repressive H3K27me3 histone modifications. Bivalency is evolutionarily conserved at developmentally important genes in germ cells but diverges at hundreds of additional loci, and evolutionary gains in bivalency have been proposed to reflect divergent somatic functions of the associated genes. Here, we sought to discover if evolutionary gains in bivalency occur selectively at genes with specific functions, and to better elucidate the role of bivalent chromatin in germ cells. By comparing genome-wide profiles for four histone modifications in spermatogenic cells of six mammalian species, we define a comprehensive set of mammalian bivalent domains and classify them based on conservation or divergence of chromatin state. We find that evolutionarily conserved bivalent regions exhibit canonical features of bivalency and maintain bivalency in embryonic stem cells. In contrast, bivalent domains emerging from a purely active or repressed ancestral chromatin state have atypical sequence and regulatory features and are frequently germ cell specific. Genes associated with these recent bivalent domains exhibit distinct somatic expression patterns that reflect their ancestral chromatin state in germ cells. Specifically, bivalent genes emerging from ancestrally active chromatin are more highly expressed in somatic tissues and are enriched for immune-related functions, while those emerging from ancestrally H3K27me3-only domains are lowly expressed in the soma and enriched for neurogenesis functions. We propose that recent bivalent regions demarcate sites of regulatory sequence change that preferentially impacts specific somatic lineages.

genomics↗

bioRxiv2023

Hem25p is a mitochondrial IPP transporter

Coenzyme Q (CoQ, ubiquinone) is an essential cellular cofactor comprised of a redox-active quinone head group and a long hydrophobic polyisoprene tail. How mitochondria access cytosolic isoprenoids for CoQ biosynthesis is a longstanding mystery. Here, via a combination of genetic screening, metabolic tracing, and targeted uptake assays, we reveal that Hem25p--a mitochondrial glycine transporter required for heme biosynthesis--doubles as an isopentenyl pyrophosphate (IPP) transporter in Saccharomyces cerevisiae. Mitochondria lacking Hem25p fail to efficiently incorporate IPP into early CoQ precursors, leading to loss of CoQ and turnover of CoQ biosynthetic proteins. Expression of Hem25p in Escherichia coli enables robust IPP uptake demonstrating that Hem25p is sufficient for IPP transport. Collectively, our work reveals that Hem25p drives the bulk of mitochondrial isoprenoid transport for CoQ biosynthesis in yeast.

biochemistry↗

bioRxiv2021

Large-scale cellular-resolution imaging of neural activity in freely behaving mice

Miniaturized microscopes for head-mounted fluorescence imaging are powerful tools for visualizing neural activity during naturalistic behaviors, but the restricted field of view of first-generation miniscopes limits the size of neural populations accessible for imaging. Here we describe a novel miniaturized mesoscope offering cellular-resolution imaging over areas spanning several millimeters in freely moving mice. This system enables comprehensive visualization of activity across entire brain regions or interactions across areas.

neuroscience↗

bioRxiv2020

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

Photosensitivity to ultraviolet (UV) light affects up to ~80% of lupus patients and can exacerbate local skin disease as well as systemic disease, including lupus nephritis. While neutrophils have been implicated in local tissue injury in lupus in response to immune complex deposition, whether and how they play a role in photosensitivity induced systemic disease is unknown. Here, we show that following skin exposure to UV light, neutrophils migrate not only to the skin, but also to the kidney, in an IL-17A-dependent manner. Kidney infiltrating neutrophils produced reactive oxygen species and their presence was associated with upregulation of endothelial adhesion molecules and inflammatory cytokines as well as the induction of kidney injury markers, including transient proteinuria. Neutrophils were responsible for inflammation and renal injury as demonstrated by experiments that inhibited neutrophil mobilization. Exploiting a mouse model containing photoactivatable immune cells, we observed that a subset of neutrophils found in the kidney had transited through UV light-exposed skin suggesting reverse transmigration. These findings demonstrate that neutrophils mediate transient kidney injury following skin exposure to UV light and, coupled with observations identifying similar neutrophil phenotypes in human lupus, could provide a mechanistic link to explain sun-induced systemic lupus flares.

immunology↗

bioRxiv2019

The early local and systemic Type I interferon responses to ultraviolet B light exposure are cGAS dependent.

Most systemic lupus erythematosus (SLE) patients are photosensitive and ultraviolet B light (UVB) exposure worsens cutaneous disease and precipitates systemic flares of disease. The pathogenic link between skin disease and systemic exacerbations in SLE remains elusive. In an acute model of UVB-triggered inflammation, we observed that a single UV exposure triggered a striking IFN-I signature not only in the skin, but also in the blood and kidneys. The early IFN-I signature was significantly higher in female compared to male mice. The early IFN-I response in the skin was almost entirely, and in the blood partly, dependent on the presence of cGAS, as was skin inflammatory cell infiltration. Inhibition of cGAMP hydrolysis augmented the UVB-triggered IFN-I response. UVB skin exposure leads to cGAS-activation and both local and systemic IFN-I signature and could contribute to acute flares of disease in susceptible subjects such as patients with SLE.

immunology↗