Biology subjects

Han, S. Y.

Publications and source records attributed to Han, S. Y..

8 recordsLinked to original sources

bioRxiv2026

Tamoxifen and Doxorubicin Synergistically Target Estrogen Receptor beta-Mutant p53-p73 Axis, a Therapeutically Actionable Vulnerability in Triple Negative Breast Cancer

Current therapeutic regimens for triple negative breast cancer (TNBC) are not very effective in majority of patients and have serious adverse effects. Tamoxifen (Tam), a selective estrogen receptor modulator (SERM), routinely used to treat estrogen receptor alpha-positive breast cancer, has traditionally not been considered for TNBC therapy because it lacks expression of ER alpha, the canonical target of Tam. Challenging this conventional clinical paradigm, we have demonstrated, using genetic and pharmacological approaches, that Tam synergizes with DNA-damaging agent doxorubicin (Doxo) to increase cell death by both apoptosis and ferroptosis leading to growth inhibition of TNBC CDXs and PDXs expressing mutant p53. Mechanistically, these responses are dependent on ER beta-mutant p53 interaction enhanced by Tam, thereby disrupting p73-mutant p53 complex resulting in reactivation of p73 and transcriptomic reprogramming converging on apoptosis and ferroptosis. These studies demonstrate the potential for repurposing Tam with Doxo as an effective and safe therapeutic strategy to treat molecularly stratified TNBC.

cancer biology↗

bioRxiv2025

Primary Cilia Dysfunction in Brown Fat Results in Fatal Thermogenesis Failure in Neonatal Mice

Primary cilium, microtubule-based sensory organelle that has emerged as a central player in coordinating numerous signaling pathways. Although primary cilia are known to regulate cellular signaling and energy metabolism, the relationship between these roles in the context of ciliopathies and brown adipose tissue (BAT) dysfunction remains poorly understood. To elucidate the role of primary cilia in BAT, we generated Ucp1-Cre;Ift88flox/flox mice with BAT-specific ciliary loss. There were no significant differences in body size, weight, or BAT weight relative to body weight between P0 Ucp1-Cre;Ift88flox/flox and P0 Ucp1-Cre;Ift88+/+ pups. Embryos examined at E14.5 and E18.5 also showed no discernible differences in size, morphology, or histology. However, P0 Ucp1-Cre;Ift88flox/flox pups exhibited neonatal lethality caused by defective thermogenesis, despite preserved Ucp1 expression. These mice displayed markedly reduced ketone body levels in both BAT and serum, accompanied by downregulation of Hmgcs2, a key enzyme in ketogenesis. Loss of primary cilia in BAT suppressed ketogenesis and increased ROS production through HMGCS2 downregulation, ultimately impairing non-shivering thermogenesis. Remarkably, neonatal lethality of Ucp1-Cre;Ift88flox/flox pups was completely rescued by thermoneutral housing or {beta}-hydroxybutyrate supplementation. Our findings identified a previously unrecognized mechanism by which primary cilia regulate non-shivering, UCP1-independent thermogenesis via ketogenesis.

cell biology↗

bioRxiv2024

Multi-dimensional oscillatory activity of mouse GnRH neurons in vivo

The gonadotropin-releasing hormone (GnRH) neurons represent the key output cells of the neural network controlling mammalian fertility. We used GCaMP fiber photometry to record the population activity of the GnRH neuron distal projections in the ventral arcuate nucleus where they merge before entering the median eminence to release GnRH into the portal vasculature. Recordings in freely behaving intact male and female mice revealed abrupt [~]8-min duration increases in activity that correlated perfectly with the appearance of a subsequent pulse of luteinizing hormone (LH). The GnRH neuron dendrons also exhibited a low level of unchanging clustered, rapidly fluctuating baseline activity in males and throughout the estrous cycle in females. In female mice, a gradual increase in basal activity that exhibited [~]80-min oscillations began in the afternoon of proestrus and lasted for 12 h. This was associated with the onset of the LH surge that ended several hours before the fall in GCaMP signal. Abrupt 8-min duration episodes of GCaMP activity continued to occur on top of the rising surge baseline before ceasing in estrus. These observations provide the first description of GnRH neuron activity in freely behaving animals. They demonstrate that three distinct patterns of oscillatory activity occur in GnRH neurons. These are comprised of low-level rapid baseline activity, abrupt 8-min duration oscillations that drive pulsatile gonadotropin secretion and, in females, a gradual and very prolonged oscillating increase in activity responsible for the preovulatory LH surge.

physiology↗

bioRxiv2024

The GnRH pulse generator activity in mouse models of polycystic ovary syndrome

One in ten women in their reproductive age suffer from polycystic ovary syndrome (PCOS) that, alongside subfertility and hyperandrogenism, typically presents with increased luteinizing hormone (LH) pulsatility. As such, it is suspected that the arcuate kisspeptin (ARNKISS) neurons that represent the GnRH pulse generator are dysfunctional in PCOS. We used here in vivo GCaMP fiber photometry and other approaches to examine the behavior of the GnRH pulse generator in two mouse models of PCOS. We began with the peripubertal androgen (PPA) mouse model of PCOS but found that it had a reduction in the frequency of ARNKISS neuron synchronization events (SEs) that drive LH pulses. Examining the prenatal androgen (PNA) model of PCOS, we observed highly variable patterns of pulse generator activity with no significant differences detected in ARNKISS neuron SEs, pulsatile LH secretion, or serum testosterone, estradiol, and progesterone concentrations. However, an unsupervised machine learning approach identified that the ARNKISS neurons of acyclic PNA mice continued to exhibit cyclical patterns of activity similar to that of normal mice. The frequency of ARNKISS neuron SEs was significantly increased in algorithm-identified "diestrous stage" PNA mice compared to controls. In addition, ARNKISS neurons exhibited reduced feedback suppression to progesterone in PNA mice and their pituitary gonadotrophs were also less sensitive to GnRH. These observations demonstrate the importance of understanding GnRH pulse generator activity in mouse models of PCOS. The existence of cyclical GnRH pulse generator activity in the acyclic PNA mouse indicates the presence of a complex phenotype with deficits at multiple levels of the hypothalamo-pituitary-gonadal axis.

neuroscience↗

bioRxiv2023

Direct androgen receptor regulation of sexually dimorphic gene expression in the mammalian kidney

Mammalian organs exhibit distinct physiology, disease susceptibility and injury responses between the sexes. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments. Bulk RNA-seq data demonstrated sex differences were established from 4 and 8 weeks after birth under gonadal control. Hormone injection studies and genetic removal of androgen and estrogen receptors demonstrated androgen receptor (AR) mediated regulation of gene activity in PT cells as the regulatory mechanism. Interestingly, caloric restriction feminizes the male kidney. Single-nuclear multiomic analysis identified putative cis-regulatory regions and cooperating factors mediating PT responses to AR activity in the mouse kidney. In the human kidney, a limited set of genes showed conserved sex-linked regulation while analysis of the mouse liver underscored organ-specific differences in the regulation of sexually dimorphic gene expression. These findings raise interesting questions on the evolution, physiological significance, and disease and metabolic linkage, of sexually dimorphic gene activity.

developmental biology↗

bioRxiv2023

Gut barrier defects, increased intestinal innate immune response, and enhanced lipid catabolism drive lethality in N-glycanase 1 deficient Drosophila

Intestinal barrier dysfunction leads to inflammation and associated metabolic changes. However, the relative impact of infectious versus non-infectious mechanisms on animal health in the context of barrier dysfunction is not well understood. Here, we establish that loss of Drosophila N-glycanase 1 (Pngl) leads to gut barrier defects, which cause starvation and increased JNK activity. These defects result in Foxo overactivation, which induces a hyperactive innate immune response and lipid catabolism, thereby contributing to lethality associated with loss of Pngl. Notably, germ-free rearing of Pngl mutants did not rescue lethality. In contrast, raising Pngl mutants on isocaloric, fat-rich diets improved animal survival in a dosage-dependent manner. Our data indicate that Pngl functions in Drosophila larvae to establish the gut barrier, and that the immune and metabolic consequences of loss of Pngl are primarily mediated through non-infectious mechanisms.

developmental biology↗

bioRxiv2022

Epitranscriptomic Modification of MicroRNA Increases Atherosclerosis Susceptibility

Emerging evidence indicates that oxidative stress causes the hydroxylation of guanine (G) to generate 8-oxo-7,8-dihydro guanosine (8OH-G) in microRNAs (miRs), which induces the guanine-to-uracil (G-to-U) transversion and thus changes the miR targetomes. However, whether and how the 8OH-G-modified miRs are involved in vascular endothelial dysfunction and atherogenesis were unexplored. Using 8OH-G crosslinking immunoprecipitation miR sequencing (8OH-G CLIP-miR-seq), we found that 8OH-G miR-483 were among the most enriched 8OH-G miR species in ECs induced by ox-LDL. Transcriptomic profiling by RNA-seq indicated that the G-to-U transversion of miR-483 altered the original mRNA targeting efficacy and allows 8OH-G miR-483 to recognize new mRNA target sites. A reduced ratio of 8OH-G miR-483 to miR-483 in lung ECs was found in the endothelial-specific miR-483 transgenic (EC-miR-483 Tg) mice. Moreover, reduction of atherosclerosis was significant in EC-miR-483 Tg mice administrated AAV8-PCSK9 and fed an atherogenic diet. In situ miR hybridization revealed an increased 8OH-G miR-483 level in the intima of human atherosclerotic arteries. Collectively, this study demonstrates that the redox burden incurred by cardiovascular risk factors is a culprit of the miR-483 to 8OH-G miR-483 transversion. Such epitranscriptomic modification of miR-483 causes endothelial dysfunction and increases atherosclerosis susceptibility via its targetomes shift.

molecular biology↗

bioRxiv2022

Mosaic receptor-binding domain nanoparticles induce protective immunity against SARS-CoV-2 challenges

Recurrent spillovers of - and {beta}-coronaviruses (CoV) such as acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, SARS-CoV-2, and possibly human CoV (NL63, 229E, OC43, and HKU1) have caused serious morbidity and mortality worldwide. Six receptor binding domains (RBDs) derived from - and {beta}-CoV that are considered to have originated from animals and cross-infected humans were linked to proliferating cell nuclear antigen (PCNA) heterotrimeric subunits, PCNA1, PCNA2, and PCNA3. These were used to form a scaffold-based mosaic multivalent antigen, 6RBD-np. Electron microscopic and atomic force microscopic images show a ring-shaped disk with six protruding RBDs, like jewels in a crown, with a size of 40 nm. Prime-boost immunizations with 6RBD-np in BALB/c mice elicited strong, dose-dependent antibody responses. In human angiotensin converting enzyme 2-transgenic mice, the same immunization induced full-protection against SARS-CoV-2 wild type and Delta challenges, resulting in a 100% survival rate. The mosaic 6RBD-np provides a potential platform for developing a pan-CoV vaccine against newly emerging SARS-CoV-2 variants and future CoV spillovers. SignificanceDespite the arsenal of COVID-19 vaccines, hospitalization and mortality associated with SARS-CoV-2 (acute respiratory syndrome coronavirus 2) variants remain high. There is an urgent need to develop next-generation COVID vaccines that provide broad protection against diseases by current and newly emerging SARS-CoV-2 variants. In this study, six receptor binding domains (RBDs) derived from - and {beta}-CoV were linked to proliferating cell nuclear antigen (PCNA) heterotrimeric scaffolds. They assemble to create a stable mosaic multivalent nanoparticle, 6RBD-np, displaying a ring-shaped disk with six protruding antigens. The prime-boost immunization in BALB/c and human angiotensin converting enzyme 2-transgenic mice with the 6RBD-np elicited strong, dose-dependent antibody responses and induced full-protection against both the SARS-CoV-2 wild type (WT) and Delta challenges. This study provides proof-of-concept that the mosaic 6RBD-np induces 100% protection against SARS-CoV-2 WT and Delta. It provides the potential of co-displaying heterologous antigens for novel vaccine designs, which can be deployed countering future pandemics.

bioengineering↗