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Shin, D.-Y.

Publications and source records attributed to Shin, D.-Y..

4 recordsLinked to original sources
bioRxiv2024

Sequencing analysis of Helicobacter pylori infection in gastric mucosa and its progression to gastric mucosa-associated tissue (MALT) lymphoma

IntroductionThe pathogenesis of gastric mucosa-associated tissue (MALT) lymphoma is associated with Helicobacter pylori infection. Although treatment strategies and responsiveness according to the stage of gastric MALT lymphoma have been widely reported, a detailed study of the biological carcinogenic process is still required. MethodPaired, fresh tumor-adjacent normal and gastric mucosal tissue samples from 13 patients with gastric MALT lymphoma were prospectively collected. Whole exome sequencing (WES) and whole-transcriptome sequencing (WTS) data were generated. The analysis of mutations, gene fusion, gene expression, and the microbiome was stratified by H. pylori infection and disease status. ResultsSomatic mutations in TRAF3 and TNFAIP3 were identified in H. pylori-negative gastric MALT lymphoma. Fusions involving BIRC3-MALT1 (2 samples) and TBL1XR1-TP63 (1 sample with H. pylori infection) were detected. Stepwise comparative analysis of RNA expression revealed upregulation of immune response, inflammatory responses, and the NF- {kappa}B signaling pathway in H. pylori-positive MALT lymphoma cases. Pathways associated with pathogens were upregulated in H. pylori-negative MALT lymphoma cases, suggesting that infections other than H. pylori may affect lymphomagenesis. Microbiome analysis revealed that genus_Rothia was negatively correlated with alpha diversity. ConclusionA stepwise approach using diverse stages of WTS data revealed detailed pathogenic mechanisms of gastric MALT lymphoma. Chronic inflammation following infection contributes to gastric MALT lymphomagenesis in both H. pylori positive and negative cases.

bioinformatics↗
bioRxiv2023

AMLs harboring DNMT3A-destabilizing variants show increased intratumor DNA methylation heterogeneity at bivalent chromatin domains

The mechanistic link between the complex mutational landscape of de novo methyltransferase DNMT3A and the pathology of acute myeloid leukemia (AML) has not been clearly elucidated so far. A recent discovery on the catalogue of DNMT3A-destabilizing mutations throughout the DNMT3A gene as well as the oligomerization-dependent catalytic property of DNMT3A prompted us to investigate the common effect of DNMT3A-destabilizing mutations (DNMT3AINS) on the genomewide methylation patterns of AML cells. In this study, we describe the characteristics of DNMT3AINS AML methylomes through the comprehensive computational analyses on three independent AML cohorts. As a result, we show that methylomes of DNMT3AINS AMLs are considerably different from those of DNMT3AR882 AMLs in that they exhibit both locally disordered DNA methylation states and increased across-cell DNA methylation heterogeneity in bivalent chromatin domains. This increased epigenetic heterogeneity was functionally associated with heterogeneous expression of membrane-associated factors shaping stem cell niche, implying the diversification of the modes of leukemic stem cell-niche interactions. We also present that the level of methylation disorder at bivalent domains predicts the response of AML cells to hypomethylating agents through cell line- and patient-level analyses, which supports that the survival of AML cells depends on stochastic DNA methylations at bivalent domains. Altogether, our work provides a novel mechanistic model suggesting the genomic origin of the aberrant epigenomic heterogeneity in disease conditions.

cancer biology↗
bioRxiv2020

Non-canonical immune response to the inhibition of DNA methylation via stabilization of endogenous retrovirus dsRNAs

5-Aza-2'-deoxycytidine, also known as decitabine, is a DNA-methyltransferase inhibitor (DNMTi) used to treat acute myeloid leukemia (AML). Decitabine activates the transcription of endogenous retroviruses (ERV), which can induce an immune response by acting as cellular double-stranded RNAs (dsRNAs). Here, we employ an image-based screening platform to identify dsRNA-binding factors that mediate the downstream effect of ERV induction. We find that Staufen1 (Stau1) knockdown decreases the interferon signature and rescues decitabine-mediated cell death. Moreover, Stau1 directly binds to ERV RNAs and stabilizes them, together with a long non-coding RNA TINCR. We further show that TINCR enhances the interaction between Stau1 and ERV RNAs. Analysis of a clinical patient cohort reveals that AML patients with low Stau1 and TINCR expressions exhibits inferior treatment outcomes to the DNMTi therapy. Our study reveals that decitabine-mediated cell death is a consequence of complex interactions among different dsRNA-binding proteins for access to their common dsRNA targets. HIGHLIHGTSO_LIImage-based RNAi screening reveals multiple dsRBPs regulate response to decitabine C_LIO_LIStau1 binds to ERV RNAs and affects their stability and subcellular localization C_LIO_LITINCR binds to Stau1 and enhances Stau1-ERV interactions C_LIO_LIAML/MDS patients with low Stau1 and TINCR expressions show poor response to DNMTis C_LI

molecular biology↗