Biology subjects

Jin, V. X.

Publications and source records attributed to Jin, V. X..

7 recordsLinked to original sources

bioRxiv2026

EZH2 Inhibition Reshapes 3D Chromatin Architecture to Induce Immunogenic Phenotype in Small Cell Lung Cancer

BackgroundThe histone methyltransferase EZH2, enzymatic core of the trimeric polycomb repressive complex 2 (PRC2), has been shown to promote small cell lung cancer (SCLC) survival through epigenetic silencing of multiple targets including Class I MHC molecules (HLA-A/B) and DNA repair factors (SLFN11). Treatment of SCLC cells with EZH2 inhibitors in vitro can reactivate expression of these genes and result in therapeutic response to immune checkpoint inhibition (ICI) and chemotherapy. Here, we investigate the impact of EZH1/2 dual inhibition on 3D chromatin structure and its relationship to transcriptional regulation in neuroendocrine (NE) SCLC. ResultsEmploying Micro-C, a micrococcal nuclease-based 3D genome mapping technique, we show that EZH1/2 inhibition with Valemetostat induced significant changes at multiple genome organizational levels (compartment, topological associated domain, and chromatin loop) without incurring cell death in NE SCLC. Alterations in 3D genome permissive for transcriptional activation were correlated with increased chromatin accessibility (ATAC-sequencing) and expression of target genes (transcriptome profiling). Known transcription factor motif discovery revealed enrichment of non-NE motifs (e.g., REST) in regions with gained chromatin accessibility in Valemetostat-treated cells, consistent with results from gene set enrichment analysis demonstrating NE to non-neuroendocrine lineage shift. Notably, EZH1/2 inhibition reactivated Class I MHC expression by facilitating enhancer-promoter looping. ConclusionOur results demonstrate that repression of a subset of EZH2 targets including Class I MHC genes is affected through modulation of 3D genome structure to the level of chromatin looping and further support clinical investigation of EZH2 inhibition in boosting therapeutic efficacy of ICI in SCLC patients.

genomics↗

bioRxiv2025

Novel Spatial-Structural-Zero-Aware Dissimilarity Measures for Subtype Discovery Using Single Cell Hi-C Data

High-throughput single-cell Hi-C (scHi-C) technologies have opened new avenues for investigating cell-to-cell variability in the three-dimensional organization of the genome within individual nuclei. Despite their potential, analyses of scHi-C data are hindered by data sparsity, which varies substantially across cells. To address this challenge, recent methods aim to denoise scHi-C data and differentiate between two types of zero entries: structural zeros (SZs), which reflect true absence of contacts due to biological structure, and dropouts (DOs), which arise from insufficient sequencing depth. However, current dissimilarity measures used in downstream analyses, such as Euclidean distance and Kendalls tau, treat all zeros as equivalent, thus do not distinguish between SZs and DOs nor recognize the special role of SZs in capturing cell-to-cell variability. Such oversight limits the ability to accurately capture biologically meaningful differences between cells. In this study, we introduce structural-zeros-aware Kendalls tau (szKendall), a novel dissimilarity metric that explicitly incorporates the spatial structure of 2D contact matrices and leverages the presence or absence of shared SZs across cells. Through comprehensive simulations and analysis of real scHi-C datasets, we demonstrate that szKendall more effectively captures key structural features and achieves superior performance in cell clustering tasks compared to existing approaches. Our results underscore the importance of SZ-aware dissimilarity measures in advancing single-cell 3D genomics.

genomics↗

bioRxiv2025

Nuc3DMap delineates finer nucleosome-based three-dimensional chromatin architecture

Currently, there lacks a method to delineate finer nucleosome-based 3D chromatin architecture. In this study, we develop a novel computational method, nucleosome-based 3D chromatin map (Nuc3DMap), to integrate MNase-seq, Hi-C and Micro-C data. Nuc3DMap implements an ensembled LOESS-sparse Knight-Ruiz algorithm to efficiently balance nucleosome-based contact matrix and adapts a bottom-up approach to identify nano-scale chromatin organization including nucleosome-based topological domain (NucD), boundary (NucB), gap (NucG) as well as nucleosome-based chromatin interaction loci (NucIL) and chromatin loop (NucL). We evaluate Nuc3DMap on publicly available data in H1 and GM12878 cells and identify the distinct subtypes of functional NucBs and NucLs, respectively, by integrating them with more than a hundred of multi-omics modalities data. Interestingly, functional NucBs exert distinct nucleosome organizational features and different insulation capability; and Pol2-related NucLs implicated Pol2 as a noncanonical regulator in mediating gene looping and cell type specificity. Furthermore, our work systematically demonstrates the relationship between interaction intensity and transcriptional activity, unveiling an activation-like behavior of chromatin looping. Overall, Nuc3DMap represents a conceptual advancement in chromatin conformation analysis, offering a refined view of genome organization from the fundamental nucleosome level to higher-order chromatin structures, as well as serves as a foundational framework for advancing computational methods development in dissecting nano-scale 3D genome organization, enabling new discoveries and fostering innovation in chromatin organization modeling.

bioinformatics↗

bioRxiv2024

EHMT2 Inactivation in Pancreatic Epithelial Cells Shapes the Transcriptional Landscape and Inflammation Response of the Whole Pancreas

The Euchromatic Histone Methyl Transferase Protein 2 (EHMT2), also known as G9a, deposits transcriptionally repressive chromatin marks that play pivotal roles in the maturation and homeostasis of multiple organs. Recently, we have shown that EHMT2 inactivation alters growth and immune gene expression networks, antagonizing KRAS-mediated pancreatic cancer initiation and promotion. Here, we elucidate the essential role of EHMT2 in maintaining a transcriptional landscape that protects organs from inflammation. Comparative RNA-seq studies between normal postnatal and young adult pancreatic tissue from EHMT2 conditional knockout animals (EHMT2fl/fl) targeted to the exocrine pancreatic epithelial cells (Pdx1-Cre and P48Cre/+), reveal alterations in gene expression networks in the whole organ related to injury-inflammation-repair, suggesting an increased predisposition to damage. Thus, we induced an inflammation repair response in the EHMT2fl/flpancreas and used a data science-based approach to integrate RNA-seq-derived pathways and networks, deconvolution digital cytology, and spatial transcriptomics. We also analyzed the tissue response to damage at the morphological, biochemical, and molecular pathology levels. The EHMT2fl/fl pancreas displays an enhanced injury-inflammation-repair response, offering insights into fundamental molecular and cellular mechanisms involved in this process. More importantly, these data show that conditional EHMT2 inactivation in exocrine cells reprograms the local environment to recruit mesenchymal and immunological cells needed to mount an increased inflammatory response. Mechanistically, this response is an enhanced injury-inflammation-repair reaction with a small contribution of specific EHMT2-regulated transcripts. Thus, this new knowledge extends the mechanisms underlying the role of the EHMT2-mediated pathway in suppressing pancreatic cancer initiation and modulating inflammatory pancreatic diseases.

cancer biology↗

bioRxiv2024

Hi-C profiling in tissues reveals 3D chromatin-regulated breast tumor heterogeneity and tumor-specific looping-mediated biological pathways

Current knowledge in three-dimensional (3D) chromatin regulation in normal and disease states was mostly accumulated through Hi-C profiling in in vitro cell culture system. The limitations include failing to recapitulate disease-specific physiological properties and often lacking clinically relevant disease microenvironment. In this study, we conduct tissue-specific Hi-C profiling in a pilot cohort of 12 breast tissues comprising of two normal tissues (NTs) and ten ER+ breast tumor tissues (TTs) including five primary tumors (PTs), and five tamoxifen-treated recurrent tumors (RTs). We find largely preserved compartments, highly heterogeneous topological associated domains (TADs) and intensively variable chromatin loops among breast tumors, demonstrating 3D chromatin-regulated breast tumor heterogeneity. Further cross-examination identifies RT-specific looping-mediated biological pathways and suggests CA2, an enhancer-promoter looping (EPL)-mediated target gene within the bicarbonate transport metabolism pathway, might play a role in driving the tamoxifen resistance. Remarkably, the inhibition of CA2 not only impedes tumor growth both in vitro and in vivo, but also reverses chromatin looping. Our study thus yields significant mechanistic insights into the role and clinical relevance of 3D chromatin architecture in breast cancer endocrine resistance.

cancer biology↗

bioRxiv2023

Reprogramming of 3D chromatin domains by antagonizing the β-catenin/CBP interaction attenuates insulin signaling in pancreatic cancer

The therapeutic potential of targeting the {beta}-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a {beta}-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this {beta}-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the {beta}-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of the functional crosstalk between antagonizing the {beta}-catenin/CBP interaction effect changes in 3D chromatin architecture and thereby gene expression and downstream effects remains to be elucidated. Here we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after the treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1, a key insulin signaling gene, significantly impede pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.

cancer biology↗

bioRxiv2023

Integration of scHi-C and scRNA-seq data defines distinct 3D-regulated and biological-context dependent cell subpopulations

An integration of 3D chromatin structure and gene expression at single-cell resolution has yet been demonstrated. Here, we develop a computational method, a multiomic data integration (MUDI) algorithm, which integrates scHi-C and scRNA-seq data to precisely define the 3D-regulated and biological-context dependent cell subpopulations or topologically integrated subpopulations (TISPs). We demonstrate its algorithmic utility on the publicly available and newly generated scHi-C and scRNA-seq data. We then test and apply MUDI in a breast cancer cell model system to demonstrate its biological-context dependent utility. We found the newly defined topologically conserved associating domain (CAD) is the characteristic single-cell 3D chromatin structure and better characterizes chromatin domains in single-cell resolution. We further identify 20 TISPs uniquely characterizing 3D-regulated breast cancer cellular states. We reveal two of TISPs are remarkably resemble to high cycling breast cancer persister cells and chromatin modifying enzymes might be functional regulators to drive the alteration of the 3D chromatin structures. Our comprehensive integration of scHi-C and scRNA-seq data in cancer cells at single-cell resolution provides mechanistic insights into 3D-regulated heterogeneity of developing drug-tolerant cancer cells.

bioinformatics↗