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  • 1
    Online Resource
    Online Resource
    Machine Learning Sequence Modeling Identifies Gene Regulatory Responses to Bone Marrow Stromal Interactions in Multiple Myeloma
    American Society of Hematology ; 2023
    In:  Blood Vol. 142, No. Supplement 1 ( 2023-11-02), p. 4144-4144
    Details
    In: Blood, American Society of Hematology, Vol. 142, No. Supplement 1 ( 2023-11-02), p. 4144-4144
    Abstract: Introduction Multiple myeloma (MM) is a hematological malignancy of plasma cells which affects different organs including the bone marrow. The interaction between MM and the bone marrow stromal cells (BMSC) has been shown to affect the disease progression and response to treatment (Kumar et al. Multiple myeloma. Nat. Rev. Dis. Primers, 2017). An in vitro system to isolate the signaling mechanisms between BMSC and MM cells has been developed by (Dziadowicz et al., Cancers, 2022), who co-cultured MM cell lines in transwell media (TSW) exposed to BMSC secreted factors and compared their ATAC-seq profiles to MM cell lines (MONO) in isolation without the exposure to BMSC. While some of the gene expression changes induced by the BMSC-MM crosstalk were reported in (Dziadowicz et al., Cancers, 2022), here we model the entire chromatin accessibility profiles with a DNA-sequence based machine learning model to detect the altered Transcription Factor (TF) and enhancer activity responsible for driving the gene expression changes. We used sequence-based machine learning models (Beer et al., 2020, Annu. Rev. Genom. Hum. Genet.) and applied a systematic approach to model the chromatin accessibility changes induced by the interaction of BMSC and MM cells (MM-TSW) vs. MM cell lines cultured in isolation (MM-MONO). Methods We trained gapped-kmer SVM (gkm-SVM) machine learning models on MM1S and RPMI8226 MM cell line ATAC-seq data generated by Dziadowicz et al. as well as 1270 DNase-seq chromatin accessibility profiles of various human primary tissues and cell lines (including MM1S and RPMI8226) from the ENCODE consortium. We trained gkm-SVM on the top 2000 differentially-accessible distal ATAC peaks ( & gt;2000bp from transcription start site, e.g. enhancers) to find the differential TF activity between MM-TSW and MM-MONO (Figure 1) and found the TF binding site motifs explaining the gkmSVM output kmer weight distribution (Figure 2). We also identified the set of differentially-expressed TFs and performed gene set enrichment using MSigDB. Results We found that RUNX and Ebox-binding (5‘-CACCTG-3‘) TF family members are the most active TFs in MM1S-MONO and RPMI8226-MONO enhancers (gkmSVM AUROCs~0.92). The contribution of the Ebox TFs to distal chromatin accessibility in the MM cell lines is greater than in any other ENCODE sample (n=1270). Principal Component Analysis (PCA) on distal ATAC peaks compared to promoters showed that the MM transcriptional response to BMSC is more clearly explained by the differences in enhancer activity rather than promoters. This response is driven by dysregulated activity of a set of enhancer regions in MM-TSW compared to MM-MONO (Figure 1) and our machine learning method can identify these regulatory changes (AUROC~0.90). In addition to the altered AP1 and JAK/STAT activity reported by Dziadowicz et al., we discovered that RUNX and Ebox-binding transcriptional activity are downregulated in MM cells following the interaction with BMSC (Figure 2). Although our RNA-seq analysis found differential expression of some Ebox-binding TFs such as TCF3 and ZEB1 and RUNX members, the identification of the exact TF member(s) driving these RUNX and Ebox/E2A downregulation in MM-TSW is still challenging. Furthermore, PCA analysis of the gene expression profiles of MM1S and RPMI8226 cells showed that the targets of Bone Morphogenetic Protein 2 (BMP2) are upregulated in MM-TSW (FDR & lt; 10 -28). Conclusion While some of the gene expression changes induced by the BMSC-MM interaction were reported in (Dziadowicz et al., Cancers, 2022), our modeling of the entire chromatin landscape discovered the previously unreported downregulation of RUNX and Ebox/E2A TFs in MM as the dominant response of MM interacting with BMSCs, accompanied by an upregulation of AP1 and JAK/STAT. RUNX and E2A-binding families of TFs include RUNX1/2/3, ZEB1/2, SNAI1/2 and TCF3, some of which we previously found to be strongly involved in epithelial to mesenchymal transition in gastric cancer and its invasiveness (Razavi-Mohseni et al., submitted, 2023). Bone marrow microenvironment interactions with MM are known to affect the disease progression and treatment, therefore, identifying the set of TFs driving the MM response to stroma may provide better understanding of the disease and better therapeutic opportunities.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2023-186981
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
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  • 2
    Online Resource
    Online Resource
    Data_Sheet_1.docx
    Frontiers Media SA ; 2020
    In:  Frontiers in Immunology Vol. 11 ( 2020-4-8)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 11 ( 2020-4-8)
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2020.00573
    DOI: 10.3389/fimmu.2020.00573.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2020
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  • 3
    Online Resource
    Online Resource
    Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019
    Elsevier BV ; 2022
    In:  The Lancet Vol. 400, No. 10369 ( 2022-12), p. 2221-2248
    Details
    In: The Lancet, Elsevier BV, Vol. 400, No. 10369 ( 2022-12), p. 2221-2248
    Type of Medium: Online Resource
    ISSN: 0140-6736
    URL: Article
    DOI: 10.1016/S0140-6736(22)02185-7
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 3306-6
    SSG: 5,21
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  • 4
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    Online Resource
    Abstract P28: Comprehensive Molecular Phenotyping of ARID1A -deficient Gastric Cancer Reveals Pervasive Epigenomic Reprogramming and Therapeutic Opportunities
    American Association for Cancer Research (AACR) ; 2024
    In:  Cancer Research Vol. 84, No. 8_Supplement ( 2024-04-15), p. P28-P28
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 84, No. 8_Supplement ( 2024-04-15), p. P28-P28
    Abstract: Objective Gastric cancer (GC) is a leading cause of cancer mortality, with ARID1A being the second most frequently mutated driver gene in GC. We sought to decipher ARID1A-specific GC regulatory networks and examine therapeutic vulnerabilities arising from ARID1A loss. Design Genomic profiling of GC patients including a Singapore cohort ( & gt;200 patients) was performed to derive mutational signatures of ARID1A inactivation across molecular subtypes. Single-cell transcriptomic profiles of ARID1A-mutated GCs were analyzed to examine tumor microenvironmental changes arising from ARID1A loss. Genome-wide ARID1A binding and chromatin profiles (H3K27ac, H3K4me3, H3K4me1, ATAC-seq) of gastric cell lines were generated to identify gastric-specific epigenetic landscapes regulated by ARID1A. Distinct cancer hallmarks of ARID1A-mutated GCs were converged at the genomic, single-cell, and epigenomic level, and targeted by pharmacological inhibition. Results We observed prevalent ARID1A inactivation across GC molecular subtypes, with distinct mutational signatures and linked to a NFKB-driven pro-inflammatory tumour microenvironment. ARID1A-depletion caused loss of H3K27ac activation signals at ARID1A-occupied distal enhancers, but unexpectedly gain of H3K27ac at ARID1A-occupied promoters in genes such as NFKB1 and NFKB2. Promoter activation in ARID1A-mutated GCs was associated with enhanced gene expression, increased BRD4 binding, and reduced HDAC1 and CTCF occupancy. Combined targeting of promoter activation and tumour inflammation via bromodomain and NFKB inhibitors confirmed therapeutic synergy specific to ARID1A-genomic status. Conclusion Our results suggest a therapeutic strategy for ARID1A-mutated GCs targeting both tumour-intrinsic (BRD4-assocatiated promoter activation) and extrinsic (NFKB immunomodulation) cancer phenotypes. Citation Format: Chang Xu, Kie Kyon Huang, Jia Hao Law, Joy Shijia Chua, Taotao Sheng, Natasha M. Flores, Melissa Pool Pizzi, Atsushi Okabe, Angie Lay Keng Tan, Feng Zhu, Vikrant Kumar, Xiaoyin Lu, Ana Morales Benitez, Benedict Shi Xiang Lian, Haoran Ma, Shamaine Wei Ting Ho, Kalpana Ramnarayanan, Chukwuemeka George Anene-Nzelu, Milad Razavi-Mohseni, Siti Aishah Binte Abdul Ghani, Su Ting Tay, Xuewen Ong, Ming Hui Lee, Yu Amanda Guo, Hassan Ashktorab, Duane Smoot, Shang Li, Anders Jacobsen Skanderup, Michael A. Beer, Roger Sik Yin Foo, Joel Shi Hao Wong, Kaushal Sanghvi, Wei Peng Yong, Raghav Sundar, Atsushi Kaneda, Shyam Prabhakar, Pawel Karol Mazur, Jaffer A. Ajani, Khay Guan Yeoh, Jimmy Bok-Yan So, Patrick Tan, Singapore Gastric Cancer Consortium. Comprehensive Molecular Phenotyping of ARID1A-deficient Gastric Cancer Reveals Pervasive Epigenomic Reprogramming and Therapeutic Opportunities [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P28.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.FCS2023-P28
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2024
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  • 5
    Online Resource
    Online Resource
    Machine learning identifies activation of RUNX/AP-1 as drivers of mesenchymal and fibrotic regulatory programs in gastric cancer
    Cold Spring Harbor Laboratory ; 2024
    In:  Genome Research Vol. 34, No. 5 ( 2024-05), p. 680-695
    Details
    In: Genome Research, Cold Spring Harbor Laboratory, Vol. 34, No. 5 ( 2024-05), p. 680-695
    Abstract: Gastric cancer (GC) is the fifth most common cancer worldwide and is a heterogeneous disease. Among GC subtypes, the mesenchymal phenotype (Mes-like) is more invasive than the epithelial phenotype (Epi-like). Although gene expression of the epithelial-to-mesenchymal transition (EMT) has been studied, the regulatory landscape shaping this process is not fully understood. Here we use ATAC-seq and RNA-seq data from a compendium of GC cell lines and primary tumors to detect drivers of regulatory state changes and their transcriptional responses. Using the ATAC-seq data, we developed a machine learning approach to determine the transcription factors (TFs) regulating the subtypes of GC. We identified TFs driving the mesenchymal (RUNX2, ZEB1, SNAI2, AP-1 dimer) and the epithelial (GATA4, GATA6, KLF5, HNF4A, FOXA2, GRHL2) states in GC. We identified DNA copy number alterations associated with dysregulation of these TFs, specifically deletion of GATA4 and amplification of MAPK9 . Comparisons with bulk and single-cell RNA-seq data sets identified activation toward fibroblast-like epigenomic and expression signatures in Mes-like GC. The activation of this mesenchymal fibrotic program is associated with differentially accessible DNA cis -regulatory elements flanking upregulated mesenchymal genes. These findings establish a map of TF activity in GC and highlight the role of copy number driven alterations in shaping epigenomic regulatory programs as potential drivers of GC heterogeneity and progression.
    Type of Medium: Online Resource
    ISSN: 1088-9051 , 1549-5469
    URL: Article
    DOI: 10.1101/gr.278565.123
    RVK:
    XA 10000
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2024
    detail.hit.zdb_id: 1483456-X
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    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Comprehensive molecular phenotyping of ARID1A -deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities
    BMJ ; 2023
    In:  Gut Vol. 72, No. 9 ( 2023-09), p. 1651-1663
    Details
    In: Gut, BMJ, Vol. 72, No. 9 ( 2023-09), p. 1651-1663
    Abstract: Gastric cancer (GC) is a leading cause of cancer mortality, with ARID1A being the second most frequently mutated driver gene in GC. We sought to decipher ARID1A -specific GC regulatory networks and examine therapeutic vulnerabilities arising from ARID1A loss. Design Genomic profiling of GC patients including a Singapore cohort ( 〉 200 patients) was performed to derive mutational signatures of ARID1A inactivation across molecular subtypes. Single-cell transcriptomic profiles of ARID1A -mutated GCs were analysed to examine tumour microenvironmental changes arising from ARID1A loss. Genome-wide ARID1A binding and chromatin profiles (H3K27ac, H3K4me3, H3K4me1, ATAC-seq) were generated to identify gastric-specific epigenetic landscapes regulated by ARID1A. Distinct cancer hallmarks of ARID1A -mutated GCs were converged at the genomic, single-cell and epigenomic level, and targeted by pharmacological inhibition. Results We observed prevalent ARID1A inactivation across GC molecular subtypes, with distinct mutational signatures and linked to a NFKB-driven proinflammatory tumour microenvironment. ARID1A -depletion caused loss of H3K27ac activation signals at ARID1A -occupied distal enhancers, but unexpectedly gain of H3K27ac at ARID1A-occupied promoters in genes such as NFKB1 and NFKB2 . Promoter activation in ARID1A -mutated GCs was associated with enhanced gene expression, increased BRD4 binding, and reduced HDAC1 and CTCF occupancy. Combined targeting of promoter activation and tumour inflammation via bromodomain and NFKB inhibitors confirmed therapeutic synergy specific to ARID1A -genomic status. Conclusion Our results suggest a therapeutic strategy for ARID1A -mutated GCs targeting both tumour-intrinsic (BRD4-assocatiated promoter activation) and extrinsic (NFKB immunomodulation) cancer phenotypes.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2022-328332
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2023
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  • 7
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    Online Resource
    Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities
    BMJ ; 2023
    In:  Gut Vol. 72, No. 2 ( 2023-02), p. 226-241
    Details
    In: Gut, BMJ, Vol. 72, No. 2 ( 2023-02), p. 226-241
    Abstract: Gastric cancer (GC) comprises multiple molecular subtypes. Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining multiple studies, we derived and applied a consensus Mes-GC classifier to define the Mes-GC enhancer landscape revealing disease vulnerabilities. Design Transcriptomic profiles of ~1000 primary GCs and cell lines were analysed to derive a consensus Mes-GC classifier. Clinical and genomic associations were performed across 〉 1200 patients with GC. Genome-wide epigenomic profiles (H3K27ac, H3K4me1 and assay for transposase-accessible chromatin with sequencing (ATAC-seq)) of 49 primary GCs and GC cell lines were generated to identify Mes-GC-specific enhancer landscapes. Upstream regulators and downstream targets of Mes-GC enhancers were interrogated using chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing, CRISPR/Cas9 editing, functional assays and pharmacological inhibition. Results We identified and validated a 993-gene cancer-cell intrinsic Mes-GC classifier applicable to retrospective cohorts or prospective single samples. Multicohort analysis of Mes-GCs confirmed associations with poor patient survival, therapy resistance and few targetable genomic alterations. Analysis of enhancer profiles revealed a distinctive Mes-GC epigenomic landscape, with TEAD1 as a master regulator of Mes-GC enhancers and Mes-GCs exhibiting preferential sensitivity to TEAD1 pharmacological inhibition. Analysis of Mes-GC super-enhancers also highlighted NUAK1 kinase as a downstream target, with synergistic effects observed between NUAK1 inhibition and cisplatin treatment. Conclusion Our results establish a consensus Mes-GC classifier applicable to multiple transcriptomic scenarios. Mes-GCs exhibit a distinct epigenomic landscape, and TEAD1 inhibition and combinatorial NUAK1 inhibition/cisplatin may represent potential targetable options.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2021-326483
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 80128-8
    detail.hit.zdb_id: 1492637-4
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  • 8
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    Online Resource
    Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer
    Springer Science and Business Media LLC ; 2021
    In:  Genome Medicine Vol. 13, No. 1 ( 2021-12)
    Details
    In: Genome Medicine, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2021-12)
    Abstract: Enhancers are distal cis -regulatory elements required for cell-specific gene expression and cell fate determination. In cancer, enhancer variation has been proposed as a major cause of inter-patient heterogeneity—however, most predicted enhancer regions remain to be functionally tested. Methods We analyzed 132 epigenomic histone modification profiles of 18 primary gastric cancer (GC) samples, 18 normal gastric tissues, and 28 GC cell lines using Nano-ChIP-seq technology. We applied Capture-based Self-Transcribing Active Regulatory Region sequencing (CapSTARR-seq) to assess functional enhancer activity. An Activity-by-contact (ABC) model was employed to explore the effects of histone acetylation and CapSTARR-seq levels on enhancer-promoter interactions. Results We report a comprehensive catalog of 75,730 recurrent predicted enhancers, the majority of which are GC-associated in vivo ( 〉  50,000) and associated with lower somatic mutation rates inferred by whole-genome sequencing. Applying CapSTARR-seq to the enhancer catalog, we observed significant correlations between CapSTARR-seq functional activity and H3K27ac/H3K4me1 levels. Super-enhancer regions exhibited increased CapSTARR-seq signals compared to regular enhancers, even when decoupled from native chromatin contexture. We show that combining histone modification and CapSTARR-seq functional enhancer data improves the prediction of enhancer-promoter interactions and pinpointing of germline single nucleotide polymorphisms (SNPs), somatic copy number alterations (SCNAs), and trans -acting TFs involved in GC expression. We identified cancer-relevant genes ( ING1 , ARL4C ) whose expression between patients is influenced by enhancer differences in genomic copy number and germline SNPs, and HNF4α as a master trans -acting factor associated with GC enhancer heterogeneity. Conclusions Our results indicate that combining histone modification and functional assay data may provide a more accurate metric to assess enhancer activity than either platform individually, providing insights into the relative contribution of genetic ( cis ) and regulatory ( trans ) mechanisms to GC enhancer functional heterogeneity.
    Type of Medium: Online Resource
    ISSN: 1756-994X
    URL: Article
    DOI: 10.1186/s13073-021-00970-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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