Biology subjects

Choi, J. K.

Publications and source records attributed to Choi, J. K..

8 recordsLinked to original sources

bioRxiv2026

Longitudinal transcriptomic analysis reveals adaptive transcript usage remodeling associated with PARP inhibitor resistance

Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment of ovarian and breast cancers with homologous recombination deficiency (HRD). Despite substantial initial efficacy, the frequent development of acquired resistance poses a critical clinical challenge, necessitating a deeper understanding of the underlying molecular mechanisms. While genomic profiling provides information on baseline HRD status, it is insufficient to capture the dynamic and functional adaptations accompanying resistance during treatment. In this study, we investigated the role of alternative splicing in PARPi resistance using longitudinal pre- and post-treatment RNA-sequencing data from an ovarian cancer patient cohort (n=40). We demonstrated that profiling alternative splicing dynamics and differentially used transcripts (DUTs) provides transcriptomic insights distinct from conventional differential gene expression analysis. Notably, we observed significant differences between acquired resistance (AR) and innate resistance (IR) groups. Specifically, longitudinal analysis revealed that AR tumors exhibit a distinct transcript usage pattern, characterized by an increase in canonical protein-coding transcripts involved in cell-cycle processes and a decrease in non-canonical non-coding transcripts within the homologous recombination pathway following treatment. Extending this comparison across AR and IR tumors at both pre- and post-treatment stages, these transcriptomic features were most pronounced in the AR post-treatment group. Further analysis of subsequent treatment outcomes showed that, among AR patients, greater resistance-associated transcriptomic remodeling was associated with poorer response and shorter progression-free survival. The resistance-associated transcriptomic signatures identified through longitudinal profiling were further recapitulated in an independent pre-treatment cohort (n=71; 43 AR and 28 IR), with more pronounced differences among BRCA wild-type patients. Taken together, our findings identify differential transcript usage as dynamic transcriptomic features associated with acquired PARPi resistance and establish a framework for utilizing longitudinal transcriptome dynamics to investigate the molecular basis of clinical drug resistance.

cancer biology↗

bioRxiv2024

Unveiling the influence of tumor and immune signatures on immune checkpoint therapy in advanced lung cancer

This study investigates the variability among patients with non-small cell lung cancer (NSCLC) in their responses to immune checkpoint inhibitors (ICI). Recognizing that patients with advanced-stage NSCLC rarely qualify for surgical interventions, it becomes crucial to identify biomarkers that influence responses to ICI therapy. We conducted an analysis of single-cell transcriptomes from 33 lung cancer biopsy samples, with a particular focus on 14 core samples taken before the initiation of palliative ICI treatment. Our objective was to link tumor and immune cell profiles with patient responses to ICI. We discovered that ICI non-responders exhibited a higher presence of CD4+ regulatory T cells, resident memory T cells, and TH17 cells. This contrasts with the diverse activated CD8+ T cells found in responders. Furthermore, tumor cells in non-responders frequently showed heightened transcriptional activity in the NF-kB and STAT3 pathways, suggesting a potential inherent resistance to ICI therapy. Through the integration of immune cell profiles and tumor molecular signatures, we achieved an discriminative power (AUC) exceeding 95% in identifying patient responses to ICI treatment. These results underscore the crucial importance of the interplay between tumor and immune microenvironment, including within metastatic sites, in affecting the effectiveness of ICIs in NSCLC.

bioinformatics↗

bioRxiv2023

Genomic hypomethylation in cell-free DNA predicts responses to checkpoint blockade in lung and breast cancer

Genomic hypomethylation has recently been identified as a determinant of therapeutic responses to immune checkpoint blockade (ICB). However, tumor tissue is often unattainable, and tissue-based methylation profiling suffers from low tumor purity. In this study, we developed an assay named iMethyl to estimate the genomic hypomethylation status from cell-free DNA (cfDNA) as well as tissue by deep targeted sequencing of young LINE-1 elements with > 400,000 reads per sample. iMethyl was applied to a total of 653 ICB samples encompassing lung cancer (cfDNA n=167; tissue n=137; cfDNA early during treatment n=40), breast cancer (cfDNA n=91; tissue n=50; PBMC n=50; cfDNA at progression n=44), and ovarian cancer (tissue n=74). iMethyl-tissue had better predictive power than tumor mutation burden and PD-L1 expression. Furthermore, iMethyl-liquid predicted ICB responses accurately regardless of the tumor purity of tissue samples. iMethyl-liquid was also able to monitor therapeutic responses early during treatment (3 or 6 weeks after initiation of ICB) and detect progressive hypomethylation accompanying tumor progression. In conclusion, our method allows for reliable noninvasive prediction, early evaluation, and monitoring of clinical responses to ICB therapy.

cancer biology↗

bioRxiv2023

Pan-cancer analysis reveals multifaceted roles of retrotransposon-fusion RNAs

Transposon-derived transcripts are abundant in RNA sequences, yet their landscape and function, especially for fusion transcripts derived from unannotated or somatically acquired transposons, remains underexplored. Here, we developed a new bioinformatic tool to detect transposon-fusion transcripts in RNA-sequencing data and performed a pan-cancer analysis of 10,257 cancer samples across 34 cancer types as well as 3,088 normal tissue samples. We identified 52,277 cancer-specific fusions with [~]30 events per cancer and hotspot loci within transposons vulnerable to fusion formation. Exonization of intronic transposons was the most prevalent genic fusions, while somatic L1 insertions constituted a small fraction of cancer-specific fusions. Source L1s and HERVs, but not Alus showed decreased DNA methylation in cancer upon fusion formation. Overall cancer-specific L1 fusions were enriched in tumor suppressors while Alu fusions were enriched in oncogenes, including recurrent Alu fusions in EZH2 predictive of patient survival. We also demonstrated that transposon-derived peptides triggered CD8+ T-cell activation to the extent comparable to EBV viruses. Our findings reveal distinct epigenetic and tumorigenic mechanisms underlying transposon fusions across different families and highlight transposons as novel therapeutic targets and the source of potent neoantigens.

cancer biology↗

bioRxiv2023

Genetic and transcriptomic analysis of hyphal constriction based on a novel assay method in the rice blast fungus

An ability of fungi to undergo hyphal constriction is important for fungal ecology and diseases. In the rice blast fungus, Magnaporthe oryzae, hyphal constriction is required to traverse host cell junctions through pit fields. However, little is known about genetic underpinnings of hyphal constriction, except the requirement of a mitogen-activated protein kinase, Pmk1. Here we demonstrate that a simple in vitro assay based on nitrocellulose membrane allows investigation of the genetic basis for hyphal constriction. Using the assay, we found that the constriction limit of M. oryzae hypha lies between 0.22 and 0.3 m, and that a histone modification might be involved in hyphal constriction. RNA-seq experiments combining our assay and {Delta}pmk1 showed that hyphal constriction relies on transcriptional changes of genes implicated primarily in membrane and cell wall-related cellular processes in Pmk1-dependent and/or Pmk1-independent manner. Furthermore, our assays with diverse fungal species suggest correlation between hyphal constriction and fungal lifestyles. Our study reveals that hyphal constriction can be induced without host-derived cues and provides molecular and evolutionary insights into a fundamental process to infection of host plant.

microbiology↗

bioRxiv2019

Noncoding de novo mutations contribute to autism spectrum disorder via chromatin interactions

Three-dimensional chromatin structures regulate gene expression across genome. The significance of de novo mutations (DNMs) affecting chromatin interactions in autism spectrum disorder (ASD) remains poorly understood. We generated 931 whole-genome sequences for Korean simplex families to detect DNMs and identified target genes dysregulated by noncoding DNMs via long-range chromatin interactions between regulatory elements. Notably, noncoding DNMs that affect chromatin interactions exhibited transcriptional dysregulation implicated in ASD risks. Correspondingly, target genes were significantly involved in histone modification, prenatal brain development, and pregnancy. Both noncoding and coding DNMs collectively contributed to low IQ in ASD. Indeed, noncoding DNMs resulted in alterations, via chromatin interactions, in target gene expression in primitive neural stem cells derived from human induced pluripotent stem cells from an ASD subject. The emerging neurodevelopmental genes, not previously implicated in ASD, include CTNNA2, GRB10, IKZF1, PDE3B, and BACE1. Our results were reproducible in 517 probands from MSSNG cohort. This work demonstrates that noncoding DNMs contribute to ASD via chromatin interactions.

neuroscience↗

bioRxiv2019

Convolutional neural network model to predict causal risk factors that share complex regulatory features

Major progress in disease genetics has been made through genome-wide association studies (GWASs). One of the key tasks for post-GWAS analyses is to identify causal noncoding variants with regulatory function. Here, on the basis of > 2,000 functional features, we developed a convolutional neural network framework for combinatorial, nonlinear modeling of complex patterns shared by risk variants scattered among multiple associated loci. When applied for major psychiatric disorders and autoimmune diseases, neural and immune features, respectively, exhibited high explanatory power while reflecting the pathophysiology of the relevant disease. The predicted causal variants were concentrated in active regulatory regions of relevant cell types and tended to be in physical contact with transcription factors while residing in evolutionarily conserved regions and resulting in expression changes of genes related to the given disease. We demonstrate some examples of novel candidate causal variants and associated genes. Our method is expected to contribute to the identification and functional interpretation of causal noncoding variants in post-GWAS analyses.

genetics↗

bioRxiv2017

Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers

Long interspersed nuclear element-1 (L1) retrotransposons are normally suppressed in somatic tissues mainly by DNA methylation and antiviral defense. However, L1s can be desuppressed in cancers to act as insertional mutagens and cause genomic instability by creating DNA double strand breaks and chromosomal rearrangements. Whereas the frequency of somatic L1 insertions varies greatly among individual tumors, much remains to be learned about underlying genetic, cellular, or environmental factors. Here, our pan-gastrointestinal cancer genome analyses for stomach, colorectal, and esophageal tumors identified multiple correlates of L1 activity. Clinical indicators of tumor progression, such as tumor grade and patient age, showed positive association. Potential L1 expression suppressors such as TP53 and DNMT1, a DNA methyltransferase, were inactivated in tumors with frequent L1 insertions. Importantly, tumors with high immune activity, for example, due to viral infection or high tumor-antigen load, tended to carry a low number of L1 insertions in their genomes with high expression levels of L1 suppressors such as APOBEC3s and SAMHD1. Our analysis of the transcriptional effects of intragenic retrotransposon insertions demonstrated an increased risk of gene disruption in retrotransposition-prone cancers. In particular, we found a splicing-disrupting L1 insertion in an exon of MOV10, a key L1 suppressor, which caused exon skipping with evidence of nonsense-mediated decay in a tumor with a high L1 insertion load. Our results indicate that cancer immunity may contribute to genome stability by suppressing L1 retrotransposition particularly in gastrointestinal cancers.

genomics↗