Biology subjects

Lee, Y. C. G.

Publications and source records attributed to Lee, Y. C. G..

4 recordsLinked to original sources

bioRxiv2022

Geldanamycin treatment does not result in anti-cancer activity in a preclinical model of orthotopic mesothelioma

Mesothelioma is characterised by its aggressive invasive behaviour, affecting the surrounding tissues of the pleura or peritoneum. We compared an invasive pleural model with a non-invasive subcutaneous model of mesothelioma and performed transcriptomic analyses on the tumour samples. Invasive pleural tumours were characterised by a transcriptomic signature enriched for genes associated with MEF2C and MYOCD signaling, muscle differentiation and myogenesis. Further analysis using the CMap and LINCS databases identified geldanamycin as a potential antagonist of this signature, so we evaluated its potential in vitro and in vivo. Nanomolar concentrations of geldanamycin significantly reduced cell growth, invasion, and migration in vitro. However, administration of geldanamycin in vivo did not result in significant anti-cancer activity. Our findings show that myogenesis and muscle differentiation pathways are upregulated in pleural mesothelioma which may be related to the invasive behaviour. However, geldanamycin as a single agent does not appear to be a viable treatment for mesothelioma.

cancer biology↗

bioRxiv2019

RNA transcribed from heterochromatic simple-tandem repeats are required for male fertility and histone-protamine exchange in Drosophila melanogaster

Long arrays of simple, tandemly repeated DNA sequences (known as satellites) are enriched in centromeres1 and pericentromeric regions2, and contribute to chromosome segregation and other heterochromatin functions3,4. Surprisingly, satellite DNAs are expressed in many multicellular eukaryotes, and their aberrant transcription may contribute to carcinogenesis and cellular toxicity5-7. Satellite transcription and/or RNAs may also promote centromere and heterochromatin activities 8-12. However, we lack direct evidence that satellite DNA transcripts are required for normal cell or organismal functions. Here, we show that satellite RNAs derived from AAGAG tandem repeats are transcribed in many cell types throughout Drosophila melanogaster development, enriched in neuronal tissues and testes, localized within heterochromatic regions, and important for viability. Strikingly, we find that AAGAG transcripts are necessary for male fertility and are specifically required for normal histone-protamine exchange and sperm chromatin organization. Since AAGAG RNA-dependent events happen late in spermatogenesis when the transcripts are not detected, we speculate that AAGAG RNA functions in primary spermatocytes to prime post-meiosis steps in sperm maturation. In addition to demonstrating specific essential functions for AAGAG RNAs, comparisons between closely related Drosophila species suggest that satellite repeats and their transcription evolve quickly to generate new functions.

cell biology↗

bioRxiv2019

Pericentromeric heterochromatin is hierarchically organized and spatially contacts H3K9me2/3 islands located in euchromatic genome

Membraneless pericentromeric heterochromatin (PCH) domains play vital roles in chromosome dynamics and genome stability. However, our current understanding of 3D genome organization does not include PCH domains because of technical challenges associated with repetitive sequences enriched in PCH genomic regions. We investigated the 3D architecture of Drosophila melanogaster PCH domains and their spatial associations with euchromatic genome by developing a novel analysis method that incorporates genome-wide Hi-C reads originating from PCH DNA. Combined with cytogenetic analysis, we reveal a hierarchical organization of the PCH domains into distinct \"territories.\" Strikingly, H3K9me2/3-enriched regions embedded in the euchromatic genome show prevalent 3D interactions with the PCH domain. These spatial contacts require H3K9me2/3 enrichment, are likely mediated by liquid-liquid phase separation, and may influence organismal fitness. Our findings have important implications for how PCH architecture influences the function and evolution of both repetitive heterochromatin and the gene-rich euchromatin.\n\nAuthor summaryThe three dimensional (3D) organization of genomes in cell nuclei can influence a wide variety of genome functions. However, most of our understanding of this critical architecture has been limited to the gene-rich euchromatin, and largely ignores the gene-poor and repeat-rich pericentromeric heterochromatin, or PCH. PCH comprises large part of most eukaryotic genomes, forms 3D PCH domains in nuclei, and plays vital role in chromosome dynamics and genome stability. In this study, we developed a new method that overcomes the technical challenges imposed by the highly repetitive PCH DNA, and generated a comprehensive picture of its 3D organization. Combined with image analyses, we revealed a hierarchical organization of the PCH domains. Surprisingly, we showed that distant euchromatic regions enriched for repressive epigenetic marks also dynamically interact with the main PCH domains. These 3D interactions are mediated by liquid-liquid phase separation mechanisms, similar to how oil and vinegar separate in salad dressing, and can influence the fitness of individuals. Our discoveries have strong implications for how seemingly \"junk\" DNA could impact functions in the gene-rich euchromatin.

genomics↗

bioRxiv2017

Rapid evolution of gained essential developmental functions of a young gene via interactions with other essential genes

New genes originated relatively recently and are only present in a subset of species in a phylogeny. Accumulated evidence suggests that new genes, like old genes that are conserved across species, can also take on important functions and be essential for the survival and reproductive success of organisms. While there are detailed analyses of the mechanisms underlying gained fertility functions by new genes, how new genes rapidly became essential for viability remains unclear. We focused on a young retro-duplicated gene (CG7804, which we named Cocoon) in Drosophila that originated three million years ago. We found that, unlike its evolutionarily conserved and broadly expressed parental gene, Cocoon has evolved rapidly under positive selection since its birth and accumulates many amino acid divergences at functional sites from the parental gene. Despite its young age, Cocoon is essential for the survival of D. melanogaster at multiple developmental stages, including the critical embryonic stage, and its expression is essential in different tissues from its parental gene. Functional genomic analyses found that Cocoon gained multiple DNA binding targets, which regulates the expression of genes that have other essential functions and/or have multiple gene-gene interactions. Our observations suggest that Cocoon acquired essential function to survival through forming interactions that have large impacts on the gene interaction network. Our study is an important step towards deciphering the evolutionary trajectory by which new genes functionally diverge from the parental gene and become essential.

evolutionary biology↗