Biology subjects

Jang, Y.

Publications and source records attributed to Jang, Y..

41 records · Page 3Linked to original sources

bioRxiv2020

Early developmental asymmetries in cell lineage trees in living individuals

Post-zygotic mosaic mutations can be used to track cell lineages in humans. By using cell cloning and induced pluripotent cell lines, we analyzed early cell lineages in two living individuals (a patient and a control), and a postmortem human specimen. Of ten reconstructed post-zygotic divisions, none resulted in balanced contributions of daughter lineages to tissues. In both living individuals one of two lineages from the first cleavage was dominant across tissues, with 90% frequency in blood. We propose that the efficiency of DNA repair contributes to lineage imbalance. Allocation of lineages in postmortem brain correlated with anterior-posterior axis, associating lineage history with cell fate choices in embryos. Recurrence of germline variants as mosaic suggested that certain loci may be particularly susceptible to mutagenesis. We establish a minimally invasive framework for defining cell lineages in any living individual, which paves the way for studying their relevance in health and disease.

genomics↗

bioRxiv2020

Generation of tonsil organoids as an ex vivo model for SARS-CoV-2 infection

Palatine tonsil (hereinafter referred to as "tonsil") plays role in the immune systems first line of defense against foreign pathogens. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic since the infection was first reported in China in December 2019. The aim of this study was to establish tonsil epithelial cell-derived organoids and to examine their feasibility as an ex vivo model for SARS-CoV-2 infection. Using an optimized protocol, we achieved 3D tonsil organoid culture from human tonsil tissue that reflects the distinctive characteristics of the tonsil epithelium, such as its cellular composition, histologic properties, and molecular biological features. Notably, we verified that SARS-CoV-2 can infect tonsil organoids with a robust replication efficiency. Furthermore, treatment with remdesivir, an antiviral agent, effectively protected them from viral infection. Therefore, tonsil organoids could be available for investigation of SARS-CoV-2 infection-mediated pathology and for preclinical screening of novel antiviral drug candidates. One-sentence SummaryThis study established tonsil epithelial cell-derived organoids and demonstrated their feasibility as an ex vivo model for SARS-CoV-2 infection.

microbiology↗

bioRxiv2020

Cold-adapted live attenuated SARS-CoV-2 vaccine completely protects human ACE2 transgenic mice from SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has infected more than 16,000,000 people and has caused the death of more than 650,000 individuals since December 2019. A safe and effective vaccine that can provide herd immunity against SARS-CoV-2 is urgently needed to stop the spread of this virus among humans. Many human viral vaccines are live attenuated forms of viruses that elicit humoral and cellular immunity. Here, we describe the development of a cold-adapted live attenuated vaccine (SARS-CoV-2/human/Korea/CNUHV03-CA22{degrees}C/2020) by gradually adapting the growth of SARS-CoV-2 from 37{degrees}C to 22{degrees}C in Vero cells. This vaccine can be potentially administered to humans through nasal spray. Its single dose was observed to strongly induce the neutralising antibody (>640), cellular immunity, and mucosal IgA antibody in intranasally immunised K18-hACE2 mice, which are very susceptible to SARS-CoV-2 and SARS-CoV infection. The one-dose vaccinated mice were completely protected from SARS-CoV-2 infection and did not show loss of body weight, death, and the presence of virus in tissues, such as the nasal turbinates, brain, lungs, and kidneys. Taken together, the cold-adapted live attenuated SARS-CoV-2 vaccine developed by us may contribute to saving of human lives from the threat of SARS-CoV-2.

microbiology↗

bioRxiv2019

Mitigating Pandemic Risk with Influenza A Virus Field Surveillance at a Swine-Human Interface

Working overnight at a large swine exhibition, we identified an influenza A virus (IAV) outbreak in swine, nanopore-sequenced 13 IAV genomes from samples collected, and in real-time, determined that these viruses posed a novel risk to humans due to genetic mismatches between the viruses and current pre-pandemic candidate vaccine viruses (CVV). We developed and used a portable IAV sequencing and analysis platform called Mia (Mobile Influenza Analysis) to complete and characterize full-length consensus genomes approximately 18 hours after unpacking the mobile lab. Swine are important animal IAV reservoirs that have given rise to pandemic viruses via zoonotic transmission. Genomic analyses of IAV in swine are critical to understanding pandemic risk of viruses in this reservoir, and characterization of viruses circulating in exhibition swine enables rapid comparison to current seasonal influenza vaccines and CVVs. The Mia system rapidly identified three genetically distinct swine IAV lineages from three subtypes: A(H1N1), A(H3N2) and A(H1N2). Additional analysis of the HA protein sequences of the A(H1N2) viruses identified >30 amino acid differences between the HA1 portion of the hemagglutinin of these viruses and the most closely related pre-2009 CVV. All virus sequences were emailed to colleagues at CDC who initiated development of a synthetically derived CVV designed to provide an optimal antigenic match with the viruses detected in the exhibition. In subsequent months, this virus caused 13 infections in humans, and was the dominant variant virus in the US detected in 2018. Had this virus caused a severe outbreak or pandemic, our proactive surveillance efforts and CVV derivation would have provided an approximate 8 week time advantage for vaccine manufacturing. This is the first report of the use of field-derived nanopore sequencing data to initiate a real-time, actionable public health countermeasure.

microbiology↗

bioRxiv2018

H3.3K4M destabilizes enhancer epigenomic writers MLL3/4 and impairs adipose tissue development

Histone H3K4 mono-methyltransferases MLL3 and MLL4 (MLL3/4) are required for enhancer activation during cell differentiation, though the mechanism is incompletely understood. To address MLL3/4 enzymatic activity in enhancer regulation, we have generated two mouse lines: one expressing H3.3K4M, a lysine-4-to-methionine (K4M) mutation of histone H3.3 that inhibits H3K4 methylation, and the other carrying conditional double knockout of MLL3/4 enzymatic SET domains. Expression of H3.3K4M in lineage-specific precursor cells depletes H3K4 methylation and prevents adipogenesis and adipose tissue development. Mechanistically, H3.3K4M prevents enhancer activation in adipogenesis by destabilizing MLL3/4 proteins but not other Set1-like H3K4 methyltransferases. Notably, deletion of the enzymatic SET domain of MLL3/4 in lineage-specific precursor cells mimics H3.3K4M expression and prevents adipose tissue development. Interestingly, destabilization of MLL3/4 by H3.3K4M in adipocytes does not affect adipose tissue maintenance and function. Together, our findings indicate that H3.3K4M destabilizes enhancer epigenomic writers MLL3/4 and impairs adipose tissue development.

molecular biology↗