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• Single-Cell and Spatial Multi-Omics Highlight Effects of Anti-Integrin Therapy Across Cellular Compartments in Ulcerative Colitis

  This is a focused, nested case-control study within our larger cohort "Immunoprofiling of the Blood and Intestine and Creation of a Gut Cell Atlas". This sub-study is titled as "Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis”. We examined the impact of Vedolizumab (VDZ), an anti-integrin antibody therapy, on the cellular landscape of ulcerative colitis (UC). While VDZ is primarily recognized for its role in preventing lymphocyte migration to the gut, the extent of its influence on other cellular populations has not been fully characterized. We used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to profile cells from both the blood and colon tissue samples. We pooled single-cell suspensions together before running scRNA-seq and CITE-seq, and subsequently deconvoluted the samples using the freemuxlet and demuxlet algorithms and variant call files (vcf) from bulk RNA-seq. This allowed us to assign cells to individual study subjects. We compared the cellular compositions of healthy individuals to those of UC patients undergoing treatment with VDZ or mesalamine (5-aminosalicylic acid/5-ASA). Our results revealed that VDZ induces significant changes in the variety and dynamics of mononuclear phagocytes within both the bloodstream and intestinal tissue, accompanied by subtle variations in lymphocyte populations. The dbGaP submission will provide raw sequencing data and participant phenotype data regarding disease and treatment status.

  Study phs003502

• Blood DNA Methylation in Post-Acute Sequelae of COVID-19 (PASC): a Prospective Cohort Study

  Background: DNA methylation integrates environmental signals with transcriptional programs. COVID-19 infection induces changes in the host methylome. While post-acute sequelae of COVID-19 (PASC) is a long-term complication of acute illness, its association with DNA methylation is unknown. No universal blood marker of PASC, superseding single organ dysfunctions, has yet been identified. Methods: In this single center prospective cohort study, PASC, post-COVID without PASC, and healthy participants were enrolled to investigate their symptoms association with peripheral blood DNA methylation data generated with state-of-the-art whole genome sequencing (WGS). PASC-induced quality-of-life deterioration was scored with a validated instrument, SF-36. Analyses were conducted to identify potential functional roles of differentially methylated loci, and machine learning algorithms were used to resolve PASC severity. Findings: 103 patients with PASC (22.3% male, 77.7% female), 15 patients with previous COVID-19 infection but no PASC (40.0% male, 60.0% female), and 27 healthy volunteers (48.1% male, 51.9% female) were enrolled. Whole genome methylation sequencing revealed 39 differentially methylated regions (DMRs) specific to PASC, each harboring an average of 15 consecutive positions, that differentiate patients with PASC from the two control groups. Motif analyses of PASC-regulated DMRs identify binding domains for transcription factors regulating circadian rhythm and others. Some DMRs annotated to protein coding genes were associated with changes of RNA expression. Machine learning support vector algorithm and random forest hierarchical clustering reveal 28 unique differentially methylated positions (DMPs) in the genome discriminating patients with better and worse quality of life.

  Study phs003658

• Genomic Characterization of Duke Melanoma Brain Metastases

  Previous work has shown that melanoma brain metastases (MBM) have a unique molecular profile compared to extracranial metastases (ECM). Description of the biology of MBM and associations between biological features and clinical outcomes will facilitate the design of rational therapies for patients with MBM. To better characterize the molecular profile of MBM, we conducted whole exome sequencing (WES) and total RNA sequencing on MBM tissues obtained from an independent cohort of 14 patients from Duke University Medical Center. This cohort adds valuable patient samples to the field and enables strengthened investigation of somatic mutations and gene expression profiles within and between cohorts. The mutational landscape and gene expression of MBM from the Duke cohort resembled those previously reported in a previously published dataset of WES and RNA sequencing in MBM and matched ECM tissues from UT MD Anderson Cancer Center (Fischer et al., 2019 30787016). Duke MBM demonstrated similar rates of mutations in genes associated with melanoma, including BRAF, NRAS, and PTEN, as the MD Anderson cohort. Immune populations in MBM were similar between Duke and MD Anderson MBM, though Duke samples demonstrated more resting CD4+ memory T cells. The ratio of M2 to M1 macrophages in the Duke cohort was similar to that of the MD Anderson cohort. In MBM, a higher M2:M1 ratio may contribute to an immune-suppressive tumor microenvironment. Sequencing data and sample attributes from MBM tissues obtained from 14 patients from Duke University Medical Center will be available through dbGaP.

  Study phs003009

• CAGE-seq analysis of osteoblast derived from cleidocranial dysplasia human induced pluripotent stem cells

  Non-coding RNAs (ncRNAs) comprise a major portion of transcripts and serve an essential role in biological processes. Although the importance of major transcriptomes in osteogenesis has been extensively studied, the function of ncRNAs in human osteogenesis remains unclear. Previously, we developed hiPSCs from patients with cleidocranial dysplasia (CCD) caused by runt-related transcription factor 2 (RUNX2) haploinsufficiency. To gain insight into ncRNAs in osteogenesis, we surveyed differential ncRNA expression profiling and promoter differences of RUNX2 using patient-specific iPSCs and cap analysis gene expression (CAGE) technology to define the promoter landscape. Revertant iPSCs (Rev1 iPSCs) edited by CRISPR/Cas9 system to harbor mutation-corrected RUNX2 exhibited increased proximal promoter expression of RUNX2, while CCD iPSCs did not. We identified 2271 ncRNA genes with altered expression levels before and after differentiation, 31 of which showed at least 20-fold higher expression in Rev1 iPSCs. Bioinformatic analysis also categorized AC007392.3, LINC00379, RP11-122D10.1, and RP11-90J7.2 as enhancer regulatory regions, and HOXA-AS2, MIR219-2, and RP11-834C11.3 as dyadic regulatory regions of these ncRNAs. In addition, two miRNAs, termed MIR199A2 and MIR152, were found to have high enrichment of osteogenic-related terms. Upon further examination of the role of MIR152 on osteoblast differentiation, we found that MIR152 knockdown induced upregulation of ALP and COL1A1 in Saos-2 cells. Thus, ncRNAs were found to regulate the osteogenic differentiation potentials of hiPSCs that are used for bone regeneration and repair owing to their differentiation potentials. These data allow understanding ncRNA profiles of hiPSCs during osteogenesis.

  Study JGAS000248

• Innate myeloid cell sbuset-specific gene expression patterns in the human colon are altered in Crohn's disease patients

  Background: There is a heterogeneous subset innate myeloid cells, such as macrophages and dendritic cells, in the human intestinal lamina propria. Several studies have demonstrated that these cells contribute to the maintenance of gut homeostasis through induction of inflammatory responses and tolerance via cell type-specific mechanisms; whereas, disrupted innate immune responses are implicated in the pathogenesis of Crohn?s disease. However, the detailed mechanisms by which each innate myeloid subset regulates gut homeostasis and inflammation largely remains unknown. Aim: We aimed to clarify the comprehensive gene expression profiles of innate myeloid cell subsets in the lamina propria from normal human colons (NC) and the inflamed colon sites from patients with Crohn?s disease (CDi). Methods: We performed RNA-sequencing analysis and precise bioinformatics analysis on three innate myeloid cell subsets, CD14-CD11c-, CD14-CD11c+, and CD14+CD11c+CD163low cells from NC and CDi. Results: Transcriptional analysis of the three subsets from the NC showed distinct gene expression patterns and gene ontology (GO) enrichment analysis revealed the associated innate myeloid subset-specific biological process (BP) terms. In addition, changes in gene expression patterns were observed in innate myeloid subsets from CDi. Furthermore, the core GO-BP terms for the genes upregulated in the innate myeloid cells from CDi were distinct from those found in NC. Conclusion: Our data identified the innate myeloid cell subset-specific transcriptomes and the associated enriched GO-BP terms in the NC and found these patterns were altered in CDi.

  Study JGAS000127

• DNA demethylation is associated with malignant progression of low-grade gliomas

  To elucidate the mechanisms of tumor progression is key to discovering strategies for treating patients with lower-grade glioma. Thus to characterize the changes in the molecular profile during malignant progression, we performed methylation array analysis (122 tumors), whole-exome sequencing (36 tumors and matched normal samples), and RNA sequencing (31 tumors). This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression when they recurred. Nearly half of IDH-mutant glioblastomas that had progressed from lower-grade gliomas exhibited characteristic partial DNA demethylation in previously methylated genomic regions of their corresponding initial tumors, which had the glioma CpG island methylator phenotype (G-CIMP). In these glioblastomas, cell cycle-related genes were upregulated, RB and PI3K-AKT pathway genes were frequently altered. Notably, bioinformatics analysis revealed that late-replicating domain was significantly enriched in the demethylated regions that were mostly located in non-regulatory regions, suggesting that the loss of DNA methylation during malignant transformation may involve mainly passive demethylation due to a delay in maintenance of methylation during accelerated cell division. Nonetheless, a limited number of genes including IGF2BP3, which potentially drives cell proliferation, were presumed to be upregulated due to demethylation of their promoter. Thus, cell proliferation was further promoted by passive demethylation in the promoter region of these oncogenic genes. Our data indicated that demethylation of the G-CIMP profile found in a subset of recurrent gliomas reflects accelerated cell divisions accompanied by malignant transformation. Oncogenic genes activated by such epigenetic change represent potential therapeutic targets.

  Study JGAS000146

• Complex genotype-phenotype relationships shape the response to treatment of Down Syndrome Childhood Acute Lymphoblastic Leukaemia

  Extensive genetic and epigenetic variegation has been demonstrated in many malignancies. Importantly, their interplay has the potential to contribute to disease progression and treatment resistance. To shed light on the complex relationships between these different sources of intra-tumour heterogeneity, we explored their relative contributions to the evolutionary dynamics of Acute Lymphoblastic Leukaemia (ALL) in children with Down syndrome, which has particularly poor prognosis. We quantified the tumour propagating potential of genetically distinct sub-clones using serial transplantation assays and SNP-arrays. While most leukaemias were characterized by a single dominant subclone, others were highly heterogeneous. Importantly, we provide clear and direct evidence that genotypes and phenotypes with functional relevance to leukemic progression and treatment resistance can co-segregate within the disease. Hence, individual genetic lesions can be restricted to well-defined cell immunophenotypes, corresponding to different stages of the leukemic differentiation hierarchy and varied proliferation potentials. As a result of this difference in fitness, which can be accurately quantified via competitive transplantation assays, matching diagnostic, post-treatment, and relapse leukaemias can be dominated by different genotypes, including pre-leukemic clones persisting throughout the disease progression and treatment. Intriguingly, plasticity also appears to be a temporally defined property that can segregate with genotype. These results suggest that Down Syndrome ALL should be viewed as a complex matrix of cells exhibiting genetic and epigenetic heterogeneity that foster extensive clonal evolution and competition. Therapeutic intervention reshapes this ‘eco-system’ and may provide the right conditions for the preferential expansion of selected compartments and subsequently relapse.

  Study EGAS50000001287

• An autoinflammatory RIG-I variant causing Singleton-Merten Syndrome associates with small non-coding Y-RNAs

  The RNA sensor RIG-I performs a critical role in surveying the cytoplasm for the presence of viral nucleic acids and initiating the downstream anti-viral type I interferon pathway. Through recognition of specific features, such as the presence of a 5’ di/triphosphate motif or highly structured base-paired regions, RIG-I effectively differentiates between RNA of viral- and self-origin. In Singleton-Merten syndrome (SMS), gain-of-function variants in RIG-I lead to a breakdown in this surveillance system and results in aberrant sensing of self-RNAs and deleterious upregulation of type I interferons. The identity of the self-RNAs binding to gain-of-function RIG-I mutants has remained elusive and would provide a greater understanding of the aetiology of SMS. Here we used an infrared individual-nucleotide resolution UV-crosslinking and immunoprecipitation (irCLIP) approach to determine the RNA profile bound to a previously characterised ATPase-deficient SMS variant, RIG-IC268F. irCLIP identified a broad array of self-RNAs, primarily those transcribed by RNA polymerase III, that were bound to RIG-I. Subsequent native RNA immunoprecipitation confirmed a prominent and specific interaction between RIG-IC268F and Y-RNAs, a family of four structurally similar non-coding RNAs. Manipulation of Y-RNAs alone by targeting either Y-RNA transcripts or Y-RNA stabilising proteins was insufficient to negate RIG-I induce interferon, hinting at a broader profile of RNA polymerase III-derived RNAs being influential in driving the sterile activation of gain-of-function RIG-I variants.

  Study EGAS50000001660

• Impact of Glycolysis Inhibition on the Epigenome of Synovial Fluid T Cells in Juvenile Idiopathic Arthritis

  Juvenile Idiopathic Arthritis (JIA) encompasses a group of childhood-onset autoimmune conditions characterized by joint inflammation and mononuclear cell infiltration, especially of activated CD4+ memory/effector T (Tmem/Teff) cells in synovial fluid (SF). JIA CD4+ T cells exhibit a distinct inflammation-associated epigenomic profile, though the underlying molecular mechanisms remain unclear. This study investigates the role of glycolysis in shaping the epigenomic landscape of JIA SF CD4+ T cells, with a focus on H3K27ac histone modifications. Using an ex vivo model of antigen stimulation, CD4+ T cells were isolated from peripheral blood (PB) of healthy controls (HC) and synovial fluid from JIA patients. Cells were activated in vitro with anti-CD3/CD28 for 24 hours, and changes in H3K27ac were assessed by chromatin immunoprecipitation followed by sequencing (ChIP-seq). To explore the specific role of glycolysis, cells were also treated with 2-deoxyglucose (2DG), an inhibitor of glucose-6-phosphate production. This inhibition impacted both H3K27ac acetylation patterns and gene expression associated with the activated epigenomic regions. Additionally, HC CD4+ T cells were activated in vitro in the presence of 30% SF or 30% plasma from JIA patients. RNA sequencing (RNA-seq) was performed to examine SF-induced transcriptional changes, providing insight into the metabolic dysregulation and epigenomic alterations observed in JIA SF CD4+ T cells. This dataset includes ChIP-seq and RNA-seq data that collectively advance our understanding of how glycolysis and the SF environment contribute to the epigenetic and transcriptional regulation in JIA CD4+ T cells.

  Study EGAS50000000808

• Pharmacological improvement of CFTR function rescues airway epithelial homeostasis and host defense in cystic fibrosis children

  Rationale: Recent clinical trials have shown that elexacaftor/tezacaftor/ivacaftor (ETI) provides significant benefit to patients with cystic fibrosis (CF) by improving CFTR function. Despite these promising clinical findings, the specific effects on the airway inflammatory status leading to structural damage and impaired lung function, remain elusive. Objectives: We investigated the transcriptional changes at the single cell level of airway epithelial and immune cells that underlie the clinical improvement by ETI therapy in children with CF. Methods: Nasal swabs from thirteen children with CF and at least one F508del allele aged 6 to 12 years were collected at baseline and three months after initiation of ETI and subjected to scRNA-seq. In addition, we collected nasal swabs from 12 age- and sex-matched controls. Sweat chloride concentrations, spirometry and multiple breath washout were used for clinical evaluation of CF children. Measurements and main results: ETI significantly reduced sweat chloride concentrations (-52.2 ± 14.3 mmol/L, P < 0.001) and improved the lung clearance index (-1.3 ± 1.8, P < 0.05). Single cell transcriptomics revealed an impaired interferon signalling in epithelial cells of CF children at baseline, which was partially restored by ETI in conjunction with an ETI-induced increase in expression of MHC I and II encoding genes similar to control levels. Additionally, ETI markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages. Conclusions: Improvement of CFTR function by ETI restores epithelial homeostasis and reduces immune cell inflammatory responses in the upper airways of children with CF, highlighting the potential of early initiation of ETI therapy.

  Study EGAS50000000128