Biology subjects

Choi, S. S.

Publications and source records attributed to Choi, S. S..

9 recordsLinked to original sources

bioRxiv2026

Genotype and methylation interact to reconfigure transcriptional regulation in colorectal cancer

BackgroundTranscriptional regulation is shaped by both genomic variants and the environment. Yet, how the regulatory effects of genomic variants are reconfigured by dynamic epigenomic changes during tumorigenesis remains incompletely understood. MethodsWe investigated methylation context-dependent links between genotype and gene expression in colorectal cancer (CRC) using paired tumor and normal-adjacent tissue (NAT) from 80 patients, thereby controlling for germline genomic background. By integrating promoter-targeted bisulfite sequencing with RNA-seq, we systematically compared expression quantitative trait loci (eQTLs) and methylation quantitative trait loci (mQTLs). To capture regulatory complexity beyond simple mediation, we implemented a memo-eQTL framework that explicitly models genotype x DNA methylation (GxM) interactions. ResultsWe observed extensive tissue specificity in both eQTL and mQTL landscapes; tumor-specific eGenes were significantly enriched for hallmark oncogenic pathways, including WNT and MAPK signaling. Standard mediation models explained only a minority of genotype-expression relationships, whereas our explicit interaction framework revealed widespread reconfiguration of methylation-dependent genetic effects in tumors. Memo-eQTL mapping (FDR < 0.05) identified 18 NAT and 73 tumor eGenes with significant GxM interactions, and results were consistent at a more permissive threshold (FDR < 0.2). We further developed a patient-level memo-eQTL score and found that interaction-based regulatory disruption in NAT, but not in tumor, significantly correlated with clinical stage (P = 0.035). ConclusionsGenetic regulation in cancer is reorganized through context-dependent GxM interactions. Importantly, GxM signatures in NAT are specifically linked to disease progression, offering new insights into field cancerization and the clinical consequences of regulatory reprogramming in CRC.

bioinformatics↗

bioRxiv2026

Neuropeptide Receptors Harbor More Genomic Regulatory Elements in Their Loci Than the Loci of Their Ligands

The neuropeptide signaling pathway is vital for the physiology and behavior of multicellular organisms. This pathway is mediated by ligand-receptor binding, wherein neuropeptides (NPs) are often released from neurons, while their receptors (NPRs) are ubiquitously expressed in both neuronal and non-neuronal cell types. To elucidate the underlying mechanisms of this expression pattern divergence, here we dissect the genomic and epigenomic architectures of these two distinct gene classes. We first characterized the genomic architecture of NP and NPR genes to compare their total gene length, exon and intron lengths, exon counts, and number of alternatively spliced transcripts per gene. We also profiled their regulatory genomic elements including CpG islands, TATA boxes, and their overlapping antisense transcripts. These analyses were then expanded to non-human model organisms to evaluate the evolutionary conservation of the underlying mechanisms. We found that NPRs encompass larger genomic loci and encode longer transcripts than NPs. Furthermore, the increased length of NPR transcripts was driven by longer exons rather than higher exon counts. Consistently, the number of spliced variants per gene was similar between NPs and NPRs, suggesting that alternative splicing events are a minor contributor to their distinct expression patterns. At the RNA level, NPR mRNAs possess significantly longer 3'UTRs compared to NPs, indicating a greater potential for post-transcriptional gene regulation. This complexity is also mirrored at the chromatin level, where NPR loci exhibit a higher density of epigenetic marks than NPs. Together, these findings highlight the multi-layered nature of gene regulation prioritizing control at the receptor level.

genomics↗

bioRxiv2025

Transcription factors overcome the repressive impact of Polycomb-associated methylation in tumors

DNA methylation is a key epigenetic regulator often disrupted in cancer, yet how promoter methylation dynamics translate into transcriptional changes during cancer progression remains incompletely understood. Here, we employed targeted bisulfite sequencing and RNA-seq on paired tumor and non-tumor tissues from 80 Korean colorectal cancer (CRC) patients to map promoter methylation and gene expression dynamics. Promoters with high baseline methylation in non-tumor tissues tended to become hypomethylated in tumors, while those with low baseline methylation underwent partial hypermethylation. However, these changes did not consistently correlate with gene silencing or activation. Strikingly, promoters marked by Polycomb (PcG+) in non-tumor tissue were prone to hypermethylation yet often remained transcriptionally active in tumors, a paradox most prominent in transcription factor (TF) genes. In contrast, hypermethylation in PcG- promoters was more consistently associated with transcriptional repression. Our findings suggest that epigenetic plasticity at PcG+ TF gene promoters can override the typically repressive effects of DNA methylation, potentially enabling tumors to maintain or enhance the expression of key regulatory genes. This highlights the importance of PcG occupancy in shaping the functional consequences of methylation changes during colorectal tumorigenesis, warranting deeper investigation into how these epigenetic adaptations drive cancer progression.

bioinformatics↗

bioRxiv2024

Lactoferrin-Derived Peptide Chimera Induces Caspase-independent Cell Death in Multiple Myeloma

Lactoferrin-derived peptide chimera is a synthetic peptide that mimics the functional unit of lactoferrin with antibacterial activity. Antimicrobial peptides are promising candidates for cancer treatment. Although LF is known to have anticancer effects, to the best of our knowledge, its effects on multiple myeloma have not yet been studied. In this study, we explored the potential of lactoferrin-derived chimera for the treatment of multiple myeloma, a malignant clonal plasma cell disease of the bone marrow. Lactoferrin-derived chimera effectively inhibited MM1S, MM1R, and RPMI8226 multiple myeloma cell growth and induced the early and late phases of apoptosis, but not in normal peripheral blood mononuclear cells. Furthermore, lactoferrin-derived chimera modulates the relative expression of genes involved in survival, apoptosis, and mitochondrial dysfunction at the transcriptional level. Mitochondrial analysis revealed that lactoferrin-derived chimera triggered oxidative stress in multiple myeloma cells, leading to the generation of reactive oxygen species and a decline in mitochondrial membrane potential, resulting in mitochondrial dysfunction. Although lactoferrin-derived chimera did not cause caspase-dependent cell death, it induced nuclear translocation of apoptosis-inducing factor and endonuclease G, indicating the initiation of caspase-independent apoptosis. Overall, our data suggest that lactoferrin-derived chimera induces caspase-independent programmed cell death in multiple myeloma cell lines by increasing the nuclear translocation of apoptosis-inducing factor/endonuclease G. Therefore, lactoferrin-derived chimera has potential in multiple myeloma cancer therapies.

cancer biology↗

bioRxiv2023

Genome assembly of Hibiscus sabdariffa L. provides insights into biosynthetic pathways of medicinal natural products

Hibiscus sabdariffa L. is a widely cultivated herbaceous plant with diverse applications in food, tea, fiber, and medicine. In this study, we present a high-quality genome assembly of H. sabdariffa using more than 33 Gbps of high-fidelity (HiFi) long-read sequencing data at 20X coverage. The primary assembly and haplotype-resolved genomes exhibit an N50 contig length of 26.25 Mbps, 11.96 Mbps, and 14.50 Mbps, with a coverage of 141.3%, 86.0%, and 88.6%, respectively. By aligning 26 Gbps of total RNA sequencing data (PE100) extracted from leaves, we predicted 154k, 79k, and 87k genes in the respective genome. The completeness of the genomes and predicted genes was confirmed by benchmarking universal single-copy orthologs analysis on a eudicots_odb10 database, with a 99.3% complete rate for the primary assembly. The high-quality genome resource allowed the construction of genetic networks for phenylpropanoid and flavonoid metabolism, thereby facilitating the identification of candidate genes involved in the biosynthesis of key intermediates for roselle-specific medicinal natural products. Comprehensive genomic and functional analysis opens avenues for further exploration and application of valuable natural products derived from H. sabdariffa.

genomics↗

bioRxiv2021

Hepatic miR-20b promotes nonalcoholic fatty liver disease by suppressing PPARα

BackgroundNon-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and imbalances in lipid metabolism in the liver. Although nuclear receptors (NRs) play a crucial role in hepatic lipid metabolism, the underlying mechanisms of NR regulation in NAFLD remain largely unclear. MethodsUsing network analysis and RNA-seq to determine the correlation between NRs and microRNA in human NAFLD patients, we revealed that MIR20B specifically targets PPARA. MIR20B mimic and anti-MIR20B were administered to human HepG2 and Huh-7 cells and mouse primary hepatocytes as well as high fat diet (HFD)- or methionine-deficient diet (MCD)-fed mice to verify the specific function of MIR20B in NAFLD. We tested the inhibition of the therapeutic effect of a PPAR agonist, fenofibrate, by MIR20B and the synergic effect of combination of fenofibrate with anti-MIR20B. ResultsWe revealed that MIR20B specifically targets PPARA through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of MIR20B was upregulated in free fatty acid (FA)- treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of MIR20B significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, MIR20B significantly reduced FA oxidation and mitochondrial biogenesis by targeting PPARA. In MIR20B-introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of MIR20B significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Moreover, combination of fenofibrate and anti-MIR20B exhibited the synergic effect on improvement of NAFLD in MCD-fed mice. ConclusionsTaken together, our results demonstrate that the novel MIR20B targets PPARA, plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD. FundingThis research was funded by Korea Mouse Phenotyping Project (2016M3A9D5A01952411), the National Research Foundation of Korea (NRF) grant funded by the Korea government (2020R1F1A1061267, 2018R1A5A1024340, NRF-2021R1I1A2041463, 2020R1I1A1A01074940), and the Future-leading Project Research Fund (1.210034.01) of UNIST.

molecular biology↗

bioRxiv2020

Progenitor identification and SARS-CoV-2 infection in long-term human distal lung organoid cultures

The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange and is affected by disorders including interstitial lung disease, cancer, and SARS-CoV-2-associated COVID-19 pneumonia. Investigations of these localized pathologies have been hindered by a lack of 3D in vitro human distal lung culture systems. Further, human distal lung stem cell identification has been impaired by quiescence, anatomic divergence from mouse and lack of lineage tracing and clonogenic culture. Here, we developed robust feeder-free, chemically-defined culture of distal human lung progenitors as organoids derived clonally from single adult human alveolar epithelial type II (AT2) or KRT5+ basal cells. AT2 organoids exhibited AT1 transdifferentiation potential, while basal cell organoids progressively developed lumens lined by differentiated club and ciliated cells. Organoids consisting solely of club cells were not observed. Upon single cell RNA-sequencing (scRNA-seq), alveolar organoids were composed of proliferative AT2 cells; however, basal organoid KRT5+ cells contained a distinct ITGA6+ITGB4+ mitotic population whose proliferation segregated to a TNFRSF12Ahi subfraction. Clonogenic organoid growth was markedly enriched within the TNFRSF12Ahi subset of FACS-purified ITGA6+ITGB4+ basal cells from human lung or derivative organoids. In vivo, TNFRSF12A+ cells comprised ~10% of KRT5+ basal cells and resided in clusters within terminal bronchioles. To model COVID-19 distal lung disease, we everted the polarity of basal and alveolar organoids to rapidly relocate differentiated club and ciliated cells from the organoid lumen to the exterior surface, thus displaying the SARS-CoV-2 receptor ACE2 on the outwardly-facing apical aspect. Accordingly, basal and AT2 "apical-out" organoids were infected by SARS-CoV-2, identifying club cells as a novel target population. This long-term, feeder-free organoid culture of human distal lung alveolar and basal stem cells, coupled with single cell analysis, identifies unsuspected basal cell functional heterogeneity and exemplifies progenitor identification within a slowly proliferating human tissue. Further, our studies establish a facile in vitro organoid model for human distal lung infectious diseases including COVID-19-associated pneumonia.

cell biology↗

bioRxiv2020

Proteomic analysis identifies the E3 ubiquitin ligase Pdzrn3 as a regulatory target of Wnt5a-Ror signaling

Wnt5a-Ror signaling is a conserved pathway that regulates morphogenetic processes during vertebrate development, but its downstream signaling events remain poorly understood. Through a large-scale proteomic screen in mouse embryonic fibroblasts, we identified the E3 ubiquitin ligase Pdzrn3 as a regulatory target of the Wnt5a-Ror pathway. Upon pathway activation, Pdzrn3 is degraded in a {beta}-catenin-independent, ubiquitin-proteasome system-dependent manner. We developed a flow cytometry-based reporter to monitor Pdzrn3 abundance and delineated a signaling cascade involving Frizzled, Dishevelled, CK1, and GSK3 that regulates Pdzrn3 stability. Epistatically, Pdzrn3 is regulated independently of Kif26b, another Wnt5a-Ror effector. Wnt5a-dependent degradation of Pdzrn3 requires phosphorylation of three conserved amino acids within its C-terminal LNX3H domain, which acts as a bona fide Wnt5a-responsive element. Importantly, this phospho-dependent degradation is essential for Wnt5a-Ror modulation of cell migration. Collectively, this work establishes a new Wnt5a-Ror cell morphogenetic cascade involving Pdzrn3 phosphorylation and degradation.

developmental biology↗

bioRxiv2019

Highly Efficient Repair of the ΔF508 Mutation in Airway Stem Cells of Cystic Fibrosis Patients with Functional Rescue of the Differentiated Epithelia

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl- channel. CF results in multiorgan dysfunction and ultimately mortality from respiratory sequelae. Although pharmacologic approaches have demonstrated efficacy in reducing symptoms and respiratory decline, a curative treatment modality remains elusive. Gene therapy, a promising curative strategy, has been limited due to poor correction efficiencies both in vitro and in vivo. Here, we use Cas9 and adeno-associated virus 6 (AAV6) to correct the {Delta}F508 mutation (found in [~]70% of CF alleles and [~]90% of CF patients in North America) in upper airway basal stem cells (UABCs) obtained from CF and non-CF patients undergoing functional endoscopic sinus surgery (FESS). In UABCs from homozygous ({Delta}F508/{Delta}F508) and compound heterozygous ({Delta}F508/Other) CF patients, we achieved 28 {+/-} 5 % and 42 {+/-} 15% correction, respectively. In homozygous human bronchial epithelial cells (HBECs), we achieved 41{+/-} 4 % correction. Upon differentiation in air-liquid interface (ALI), cultures of corrected CF cells displayed partial restoration of CFTRinh-172 sensitive Cl- currents relative to non-CF controls: 31{+/-} 5 % in UABCs and 51 {+/-} 3 % in HBECs (both from subjects homozygous for {Delta}F508 CFTR). Finally, gene edited cells embedded successfully and retained expression of cytokeratin 5 (KRT5), a basal cell marker, on a FDA-approved porcine small intestinal submucosal (pSIS) membrane previously shown to improve re-mucosalization after FESS. In summary, we present an efficient, feeder-free, selection-free and clinically compatible approach to generate cell-based therapies for CF from autologous airway stem cells. This approach represents a first step towards developing patient-specific autologous airway stem cell transplant as a curative treatment for CF.

bioengineering↗