Biology subjects

Kim, S. Y.

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

7 recordsLinked to original sources

bioRxiv2018

TrkB activation during a critical period mimics the protective effects of early visual experience on the stability of receptive fields in adult superior colliculus

During a critical period in postnatal development, spontaneous and evoked retinal activity shape nascent visual pathways in an adaptive fashion. Visual experience increases transcription of the neurotrophin BDNF, activating the BDNF receptor TrkB, which promotes maturation of parvalbumin (PV) positive inhibitory interneurons, a process thought to open a critical period for ocular dominance plasticity in visual cortex. Development of perineuronal nets around PV neurons limits plasticity, ending the critical period and restricting adult plasticity. Another form of critical period plasticity is receptive field (RF) refinement. Spontaneous activity alone is sufficient for spatial refinement of visual receptive fields in superior colliculus (SC) and visual cortex (V1), but visual experience during an early critical period is necessary to maintain inhibitory synapses and stabilize RFs in adulthood (Carrasco et al. 2005, 2011; Carrasco & Pallas 2006; Balmer & Pallas 2015a). We report here that deprivation-induced RF enlargement in adulthood has a behavioral consequence; it impairs fear responses to looming objects in mice and hamsters. The mechanism through which early experience protects RFs from deprivation-induced loss of inhibition in adulthood is unknown. Given that the loss of RF refinement in SC does not occur until adulthood, and that inhibitory PV neurons and perineuronal nets are rare in SC, we asked whether or not BDNF-TrkB signaling was involved. We find that early TrkB activation is necessary and sufficient to maintain visual RF refinement in adulthood, suggesting a common signaling pathway for maturation of inhibition across neuronal subtypes and locations within the visual pathway.\n\nSignificance StatementReceptive field refinement in superior colliculus (SC) differs from more commonly studied examples of critical period plasticity in visual pathways in that it does not require visual experience to occur; rather spontaneous activity is sufficient. Maintenance of refinement requires brief, early exposure to light to stabilize inhibition beyond puberty. This type of inhibitory plasticity must not depend on parvalbumin (PV)-containing GABAergic interneurons or on the formation of perineuronal nets, because these are very uncommon in SC. Nonetheless, we find that TrkB activation during a critical period can substitute for visual experience in maintaining receptive field refinement into adulthood, and that this maintenance is beneficial to visual survival behaviors. Thus, multiple types of plasticity converge on the same neurotrophin-dependent signaling cascade.

neuroscience↗

bioRxiv2018

An integrative systems biology and experimental approach identifies convergence of epithelial plasticity, metabolism, and autophagy to promote chemoresistance

The evolution of therapeutic resistance is a major cause of death for patients with solid tumors. The development of therapy resistance is shaped by the ecological dynamics within the tumor microenvironment and the selective pressure induced by the host immune system. These ecological and selective forces often lead to evolutionary convergence on one or more pathways or hallmarks that drive progression. These hallmarks are, in turn, intimately linked to each other through gene expression networks. Thus, a deeper understanding of the evolutionary convergences that occur at the gene expression level could reveal vulnerabilities that could be targeted to treat therapy-resistant cancer. To this end, we used a combination of phylogenetic clustering, systems biology analyses, and wet-bench molecular experimentation to identify convergences in gene expression data onto common signaling pathways. We applied these methods to derive new insights about the networks at play during TGF-{beta}-mediated epithelial-mesenchymal transition in a lung cancer model system. Phylogenetics analyses of gene expression data from TGF-{beta} treated cells revealed evolutionary convergence of cells toward amine-metabolic pathways and autophagy during TGF-{beta} treatment. Using high-throughput drug screens, we found that knockdown of the autophagy regulatory, ATG16L1, re-sensitized lung cancer cells to cancer therapies following TGF-{beta}-induced resistance, implicating autophagy as a TGF-{beta}-mediated chemoresistance mechanism. Analysis of publicly-available clinical data sets validated the adverse prognostic importance of ATG16L expression in multiple cancer types including kidney, lung, and colon cancer patients. These analyses reveal the usefulness of combining evolutionary and systems biology methods with experimental validation to illuminate new therapeutic vulnerabilities.

cancer biology↗

bioRxiv2018

CRISPRCloud2: A cloud-based platform for deconvoluting CRISPR screen data

The simplicity and cost-effectiveness of CRISPR technology have made high-throughput pooled screening approaches available to many. However, the large amount of sequencing data derived from these studies yields often unwieldy datasets requiring considerable bioinformatic resources to deconvolute data; a feature which is simply not accessible to many wet labs. To address these needs, we have developed a cloud-based webtool CRISPRCloud2 that provides a state-of-the-art accuracy in mapping short reads to CRISPR library, a powerful statistical test that aggregates information across multiple sgRNAs targeting the same gene, a user-friendly data visualization and query interface, as well as easy linking to other CRISPR tools and bioinformatics resources for target prioritization. CRISPRCloud2 is a one-stop shop for labs analyzing CRISPR screen data.

bioinformatics↗

bioRxiv2018

Widespread transcriptional scanning in testes modulates gene evolution rates

A long-standing question in molecular biology relates to why the testes express the largest number of genes relative to all other organs. Here, we report a detailed gene expression map of human spermatogenesis using single-cell RNA-Seq. Surprisingly, we found that spermatogenesis-expressed genes contain significantly fewer germline mutations than unexpressed genes, with the lowest mutation rates on the transcribed DNA strands. These results suggest a model of transcriptional scanning to reduce germline mutations by correcting DNA damage. This model also explains the rapid evolution in sensory- and immune-defense related genes, as well as in male reproduction genes. Collectively, our results indicate that widespread expression in the testes achieves a dual mechanism for maintaining the DNA integrity of most genes, while selectively promoting variation of other genes.

evolutionary biology↗

bioRxiv2018

A testosterone metabolite 19-hydroxyandrostenedione induces neuroendocrine trans-differentiation of prostate cancer cells via an ectopic olfactory receptor

Olfactory receptor OR51E2, also known as a Prostate Specific G-Protein Receptor, is highly expressed in prostate cancer but its function is not well understood. Through in silico and in vitro analyses, we identified 24 agonists and 1 antagonist for this receptor. We detected that agonist 19-hydroxyandrostenedione, a product of the aromatase reaction, is endogenously produced upon receptor activation. We characterized the effects of receptor activation on metabolism using a prostate cancer cell line and demonstrated decreased intracellular anabolic signals and cell viability, induction of cell cycle arrest, and increased expression of neuronal markers. Furthermore, upregulation of neuron-specific enolase by agonist treatment was abolished in OR51E2-KO cells. The results of our study suggest that OR51E2 activation results in neuroendocrine trans-differentiation. These findings reveal a new role for OR51E2 and establish this G-protein coupled receptor as a novel therapeutic target in the treatment of prostate cancer.\n\nSignificanceProstate cancer is the second most common cancer in men. Most deaths from prostate cancer are due to the progression of localized disease into metastatic, castration-resistant prostate cancer characterized by increased number of neuroendocrine-like cells. These neuroendocrine-like cells are non-proliferating, terminally differentiated cells. Olfactory receptor OR51E2, also known as a Prostate Specific G-Protein Receptor, is highly expressed in prostate cancer, and its expression correlates with disease progression. Here, we identify and validate novel endogenous ligands for this receptor. We show that activation of OR51E2 by newly-discovered prostate cancer-relevant agonists facilitates cellular transformation, resulting in neuroendocrine trans-differentiation, a characteristic phenotype of castrate resistant prostate cancer. Our results establish this G-protein coupled receptor as a novel and therapeutic target for castration-resistant prostate cancer.\n\nHighlightsO_LIDiscovery of novel agonists for olfactory receptor OR51E2/PSGR highly relevant to prostate cancer pathology\nC_LIO_LIActivation of OR51E2 receptor by agonist N-acetyl-N-formyl-5-methoxykynurenamine (AFMK) results in release of 19-hydroxyandrostenedione (19-OH AD) from the prostate cancer cells indicating its endogenous production\nC_LIO_LIActivation of OR51E2 receptor by 19-OH AD, AFMK, and propionic acid decreases anabolic and proliferative signals\nC_LIO_LIActivation of OR51E2 receptor by 19-OH AD and AFMK increases markers specific for neuroendocrine trans-differentiation (NEtD)\nC_LIO_LIAblation of the OR51E2 gene in prostate cancer cells treated with agonist 19-OH AD significantly reduces neuron-specific enolase\nC_LI

cancer biology↗

bioRxiv2017

SAVE: A secure cloud-based pipeline for CRISPR pooled screen deconvolution

We present a user-friendly, cloud-based, data analysis pipeline for the deconvolution of pooled screening data. This tool, termed SAVE for Screening Analysis Visual Explorer, serves a dual purpose of extracting, clustering and analyzing raw next generation sequencing files derived from pooled screening experiments while at the same time presenting them in a user-friendly way on a secure web-based platform. Moreover, SAVE serves as a useful web-based analysis pipeline for reanalysis of pooled CRISPR screening datasets. Taken together, the framework described in this study is expected to accelerate development of web-based bioinformatics tool for handling all studies which include next generation sequencing data. SAVE is available at http://save.nrihub.org.

bioinformatics↗

bioRxiv2016

PRDX6 inhibits neurogenesis of neural precursor cells through downregulation of wdfy1 mediated TLR4 signal

Impaired neurogenesis has been associated with brain disorders. The role of peroxiredoxin 6 (PRDX6) in the neurodegenerative diseases is very controversial. To demonstrate the role of PRDX6 in neurogenesis, we compared neurogenesis ability and studied the molecular mechanisms. It was found that the neurogenesis of neural stem cells and expression of the marker protein were lowered in PRDX6 Tg-mice compared with non-tg mice. Moreover, the expression of wdfy1 was dramatically decreased in PRDX6-Tg mice, also, we observed that wdfy1 siRNA decreases the differentiation ability of primary neural stem cells to astrocyte and neuronal cells as well as PC12 cells. However, knockdown of PRDX6 recovered neurogenesis in the brain of PRDX6-Tg mice as well as PC-12 cells. We also showed that TLR4 was dramatically reduced in PRDX6 Tg mice as well as PC-12 cells and PRDX6 overexpression reduced neurogenesis was rescued after treatment of TLR4 siRNA. We further found that reduced TLR4 expression and neurogenesis was reversed in the neuron from PRDX6-Tg mice as well as PC12 cells by introduction of wdfy1 plasmid. Moreover, TLR4 siRNA reduced neurogenesis and wdfy1 expression. This study indicated that PRDX6 inhibits neurogenesis of neural precursor cells through TLR4 dependent downregulation of wdfy1.

developmental biology↗