Biology subjects

Hong, J. J.

Publications and source records attributed to Hong, J. J..

5 recordsLinked to original sources

bioRxiv2026

Cardiomyocyte pyruvate dehydrogenase kinase 1 knockout activates Rho-mediated remodeling and decreases fatty acyl availability in female mice

Pyruvate dehydrogenase kinase 1 (PDK1) inhibits pyruvate dehydrogenase (PDH) and therefore may regulate the balance between glucose and fatty acid oxidation in cardiomyocytes. We assessed metabolism and function in tamoxifen-inducible, cardiomyocyte-specific Pdk1 knockout (Pdk1cKO) mice, including both males and females fed a high fat diet, to resolve the role of PDK1 in the heart. Female, but not male, Pdk1cKO hearts showed the expected increase in cardiac PDH activity. Though cardiac function was largely preserved, female Pdk1cKO hearts had smaller left ventricles. Proteomics and phosphoproteomics revealed no change in classical hypertrophic markers but downregulated aerobic respiration alongside upregulated Ca2+ handling and Rho signalling, suggesting metabolic remodeling with altered cardiomyocyte contractility and cytoarchitecture in Pdk1cKO hearts. Concordantly, lipidomics revealed membrane remodeling marked by elevated saturated phosphatidylcholine in female Pdk1cKO hearts and decreased triacylglycerols, free fatty acids and fatty acid uptake proteins (CD36, FABP3). These findings reveal novel, female-predominant cardiometabolic roles for PDK1.

molecular biology↗

bioRxiv2023

MYCN driven oncogenesis involves cooperation with WDR5 to activate canonical MYC targets and G9a to repress differentiation genes

MYCN activates canonical MYC targets involved in ribosome biogenesis, protein synthesis and represses neuronal differentiation genes to drive oncogenesis in neuroblastoma (NB). How MYCN orchestrates global gene expression remains incompletely understood. Our study finds that MYCN binds promoters to up-regulate canonical MYC targets but binds to both enhancers and promoters to repress differentiation genes. MYCN-binding also increases H3K4me3 and H3K27ac on canonical MYC target promoters and decreases H3K27ac on neuronal differentiation gene enhancers and promoters. WDR5 is needed to facilitate MYCN promoter binding to activate canonical MYC target genes, whereas MYCN recruits G9a to enhancers to repress neuronal differentiation genes. Targeting both MYCNs active and repressive transcriptional activities using both WDR5 and G9a inhibitors synergistically suppresses NB growth. We demonstrate that MYCN cooperates with WDR5 and G9a to orchestrate global gene transcription. The targeting of both these cofactors is a novel therapeutic strategy to indirectly target the oncogenic activity of MYCN.

cancer biology↗

bioRxiv2022

A rapid platform for 3D patient-derived cutaneous neurofibroma organoid establishment and screening

Localized cutaneous neurofibromas (cNFs) are benign tumors that arise in the dermis of patients affected by Neurofibromatosis Type 1 syndrome (NF1). cNFs are fundamentally benign lesions: they do not undergo malignant transformation or metastasize. Nevertheless, in NF1 patients, they can cover a significant proportion of the body, with some individuals developing hundreds to thousands of lesions. cNFs can cause pain, itching, and disfigurement with substantial socio-emotional repercussions. To date, surgical removal or laser desiccation are the only treatment options, but can result in scarring and the leave a potential for regrowth. To support drug discovery efforts focused on identifying effective systemic therapies for cNF, we introduce an approach to routinely establish and screen cNF tumor organoids. We optimized conditions to support ex vivo growth of genomically-diverse cNFs. Patient-derived cNF organoids closely recapitulate the molecular and cellular heterogeneity of these tumors as measured by immunohistopathology, DNA methylation, RNA-seq and flow cytometry. Our tractable patient-derived cNF organoid platform enables rapid screening of hundreds of compounds in a patient- and tumor-specific manner.

systems biology↗

bioRxiv2022

Cascades of neuronal plasticity in the macaque visual cortex

Primates readily learn new visual objects, with neurons in the inferior temporal cortex exhibiting diminished visual responses to familiar stimuli. The mechanisms of visual plasticity expressed within a neural population are largely unknown. Here we used chronic microwire electrodes in a face-selective cortical area in the macaque to longitudinally track cohorts of neurons across several weeks of exposure to novel faces. Neurons showed gradual adaptation in their late-phase visual responses, with cell-specific time constants ranging from two to twenty days. These time constants were governed by the number of testing days rather than by the cumulative number of stimulus exposures. This gradual buildup of altered visual responses may serve as an internal and graded mark of stimulus familiarity, a central component of visual recognition.

neuroscience↗

bioRxiv2020

Soluble Spike DNA vaccine provides long-term protective immunity against SAR-CoV-2 in mice and nonhuman primates

The unprecedented and rapid spread of SARS-CoV-2 has motivated the need for a rapidly producible and scalable vaccine. Here, we developed a synthetic soluble SARS-CoV-2 spike (S) DNA-based vaccine candidate, GX-19. In mice, immunization with GX-19 elicited not only S-specific systemic and pulmonary antibody responses but also Th1-biased T cell responses in a dose-dependent manner. GX-19 vaccinated nonhuman primate seroconverted rapidly and exhibited detectable neutralizing antibody response as well as multifunctional CD4+ and CD8+ T cell responses. Notably, when the immunized nonhuman primates were challenged at 10 weeks after the last vaccination with GX-19, they did not develop fever and reduced viral loads in contrast to non-vaccinated primates as a control. These findings indicate that GX-19 vaccination provides durable protective immune response and also support further development of GX-19 as a vaccine candidate for SARS-CoV-2 in human clinical trials.

immunology↗