Biology subjects

Cho, Y.-J.

Publications and source records attributed to Cho, Y.-J..

6 recordsLinked to original sources

bioRxiv2024

Ezh2 Delays Activation of Differentiation Genes During Normal Cerebellar Granule Neuron Development and in Medulloblastoma

Medulloblastoma (MB) is the most common malignant brain tumour in children. The Sonic Hedgehog (SHH)-medulloblastoma subtype arises from the cerebellar granule neuron lineage. Terminally differentiated neurons are incapable of undergoing further cell division, so an effective treatment for this tumour could be to force neuronal differentiation. Differentiation therapy provides a potential alternative for patients with medulloblastoma who harbor mutations that impair cell death pathways (TP53), which is associated a with high mortality. To this end, our goal was to explore epigenetic regulation of cerebellar granule neuron differentiation in medulloblastoma cells. Key regulators were discovered using chromatin immunoprecipitation with high-throughput sequencing. DNA-bound protein and chromatin protein modifications were investigated across all genes. We discovered that Ezh2-mediated tri-methylation of the H3 histone (H3K27me3), occurred on more than half of the 787 genes whose transcription normally increases as granule neurons terminally differentiate. Conditional knockout of Ezh2 led to early initiation of differentiation in granule neuron precursors (GNPs), but only after cell cycle exit had occurred. Similarly, in MB cells, neuronal differentiation could be induced by preventing H3K27me3 modifications using an Ezh2 inhibitor (UNC1999), but only when UNC1999 was combined with forced cell cycle exit driven by a CDK4/6 inhibitor (Palbociclib). Ezh2 emerges as a powerful restraint upon post-mitotic differentiation during normal GNP development and combination of Ezh2 inhibition with cell cycle exit leads to MB cell differentiation.

cancer biology↗

bioRxiv2024

Elongation factor P controls ribosomal frameshift of a Salmonella antimicrobial resistance gene

Ribosomes translate mRNAs by matching every 3-nucleotide sequence in mRNA, producing the corresponding proteins. As the amino acid sequence directly dictates the activity of the protein, frameshifts often lead to unexpected effects. Here, ribosome profiling reveals that the intracellular pathogen Salmonella Typhimurium suppresses frameshift in the ugtL antimicrobial resistance gene during translation. This suppression of frameshift is mediated by a ribosome pause occurring in a newly-identified overlapping gene, serving as a non-slip bump. Given that the pause site contains a poly-proline motif and can be resolved by elongation factor P, the removal of the ribosome pause by substituting the motif induces ribosome slippage in ugtL, resulting in UgtL frameshifted protein production. This renders Salmonella sensitive to antimicrobial peptides but, in turn, protects the MgtC virulence factor from the FtsH-mediated proteolysis, indicating that elongation factor P-dependent ribosome pause is required for controlling both full antimicrobial resistance and mouse virulence. These findings reveal a new regulatory mechanism in which ribosome pause controls the production of two different protein isoforms by suppressing ribosome slippage-mediated frameshift.

microbiology↗

bioRxiv2024

A HigB-like toxin promotes non-replicating Salmonella inside macrophages by inhibiting ribonuclease III

Many bacteria are often resistant to antibiotic treatment because they can slow down their growth rate, thereby attenuating the drugs effectiveness. A similar growth-rate control is observed in pathogens that infect and persist inside their hosts. The bacterial toxin-antitoxin (TA) system serves as a non-heritable phenotypic switch by slowing down growth through the expression of a toxin component. Here, we investigated a HigB-like type II toxin from the intracellular bacterial pathogen Salmonella Typhimurium. Unlike other HigB-like toxins that cleave ribosome-bound mRNAs, it does not exhibit endoribonuclease activity. Instead, it inhibits ribonuclease III, which mediates the initial cleavage for rRNA processing, by directly binding to the dsRNA-binding domain of RNase III, thereby decreasing ribosome assembly and bacterial growth. Given that the formation of HigB-like toxin-mediated non-replicating Salmonella within macrophages is RNase III-dependent, persister formation by inhibiting RNase III is a newly identified strategy for pathogens to survive within host cells.

microbiology↗

bioRxiv2023

Live Malassezia strains isolated from the mucosa of patients with ulcerative colitis

The human gut is inhabited by a complex ecosystem of diverse microorganisms. While most studies on the gut microbiota have focused on bacteria, accumulating evidence has underscored the role of the mycobiota in inflammatory bowel disease (IBD). This study is the first to isolate and characterize live Malassezia globosa strains from the intestinal mucosa of patients with ulcerative colitis. Malassezia species primarily inhabit the human skin. We therefore compared the M. globosa gut isolates with the M. globosa skin isolates and noted a striking disparity between them. The gut isolates led to a greater exacerbation of colitis in mice. Transcriptome analysis revealed that the gut isolates were more sensitive to normoxia than the skin isolates, suggesting adaptation to hypoxia prevalent in the intestinal environment. These findings provide novel insights into the potential impact of M. globosa on the pathogenesis of IBD and the influence of niche-specific adaptations on its virulence.

microbiology↗

bioRxiv2019

A novel totivirus alters gene expression and vacuolar morphology in Malassezia cells and induces a TLR3-mediated inflammatory immune response

Most fungal viruses have been identified in plant pathogens, whereas the presence of viral particles in human pathogenic fungi is less well studied. In the present study, we observed extrachromosomal double-stranded RNA (dsRNA) segments in various clinical isolates of Malassezia species. Malassezia is the most dominant fungal genus on the human skin surface, and species in this group are considered etiological factors of various skin diseases including dandruff, seborrheic dermatitis, and atopic dermatitis. We identified novel dsRNA segments, and our sequencing results revealed that the virus, named MrV40, belongs to the Totiviridae family and contains an additional satellite dsRNA segment encoding a novel protein. The transcriptome of virus-infected Malassezia restricta cells was compared to that of virus-cured cells, and the results showed that transcripts involved in ribosomal biosynthesis were downregulated and those involved in energy production and programmed cell death were upregulated. Moreover, transmission electron microscopy revealed significantly larger vacuoles in virus-infected M. restricta cells, indicating that MrV40 infection dramatically altered M. restricta physiology. Our analysis also revealed that viral nucleic acid from MrV40 induced a TLR3-mediated inflammatory immune response in bone marrow-derived dendritic cells, suggesting that a viral element contributes to the pathogenicity of Malassezia. ImportanceMalassezia is the most dominant fungal genus on the human skin surface and is associated with various skin diseases including dandruff and seborrheic dermatitis. Among Malassezia species, Malassezia restricta is the most widely observed species on the human skin. In the current study, we identified a novel dsRNA virus, named MrV40, in M. restricta and characterized the sequence and structure of the viral genome along with an independent satellite dsRNA viral segment. Moreover, expression of genes involved in ribosomal synthesis and programmed cell death was altered, indicating that virus infection affected the physiology of the fungal host cells. Our data also showed that the viral nucleic acid from MrV40 induces a TLR3-mediated inflammatory immune response in bone marrow-derived dendritic cells, indicating that a viral element likely contributes to the pathogenicity of Malassezia. This is the first study to identify and characterize a novel mycovirus in Malassezia.

microbiology↗

bioRxiv2018

Optimal diameter reduction ratio of acinar airways in human lungs

In the airway network of a human lung, the airway diameter gradually decreases through multiple branching. The diameter reduction ratio of the conducting airways that transport gases without gas exchange is 0.79, but this reduction ratio changes to 0.94 in acinar airways beyond transitional bronchioles. While the reduction in the conducting airways was previously rationalized on the basis of Murrays law, our understanding of the design principle behind the acinar airways has been far from clear. Here we elucidate that the change in gas transfer mode is responsible for the transition in the diameter reduction ratio. The oxygen transfer rate per unit surface area is maximized at the observed geometry of acinar airways, which suggests the minimum cost for the construction and maintenance of the acinar airways. The results revitalize and extend the framework of Murrays law over an entire human lung.

bioengineering↗