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Background Epigenomic studies that use next generation sequencing experiments typically rely on the alignment of reads to a reference sequence. However, because of genetic diversity and the diploid nature of the human genome, we hypothesize that using a generic reference could lead to incorrectly mapped reads and bias downstream results. Results We show that accounting for genetic variation using a modified reference genome or a de novo assembled genome can alter histone H3K4me1 and H3K27ac ChIP-seq peak calls either by creating new personal peaks or by the loss of reference peaks. Using permissive cutoffs, modified reference genomes are found to alter approximately 1% of peak calls while de novo assembled genomes alter up to 5% of peaks. We also show statistically significant differences in the amount of reads observed in regions associated with the new, altered, and unchanged peaks. We report that short insertions and deletions (indels), followed by single nucleotide variants (SNVs), have the highest probability of modifying peak calls. We show that using a graph personalized genome represents a reasonable compromise between modified reference genomes and de novo assembled genomes. We demonstrate that altered peaks have a genomic distribution typical of other peaks. Conclusions Analyzing epigenomic datasets with personalized and graph genomes allows the recovery of new peaks enriched for indels and SNVs. These altered peaks are more likely to differ between individuals and, as such, could be relevant in the study of various human phenotypes.

The role of the pro-inflammatory cytokine IL-17 in the pathogenesis of numerous inflammatory disorders is well-documented, but conflicting results are reported for its role in diabetic nephropathy. Here we examined the role of IL-17 signalling in a model of streptozotocin-induced diabetic nephropathy through IL-17 knockout mice, administration of neutralising monoclonal anti-IL-17 antibody and in vitro examination of gene expression of renal tubular cells and podocytes under high glucose conditions with or without recombinant IL-17. IL-17 deficient mice were protected against progression of diabetic nephropathy, exhibiting reduced albuminuria, glomerular damage, macrophage accumulation and renal fibrosis at 12 weeks and 24 weeks. Administration of anti-IL-17 monoclonal antibody to diabetic wild-type mice was similarly protective. IL-17 deficiency also attenuated up-regulation of pro-inflammatory and pro-fibrotic genes including IL-6, TNF-α, CCL2, CXCL10 and TGF-β in diabetic kidneys. In vitro co-stimulation with recombinant IL-17 and high glucose were synergistic in increasing the expression of pro-inflammatory genes in both cultured renal tubular cells and podocytes. We conclude that absence of IL-17 signalling is protective against streptozotocin-induced diabetic nephropathy, thus implying a pro-inflammatory role of IL-17 in its pathogenesis. Targeting the IL-17 axis may represent a novel therapeutic approach in the treatment of this disorder.

Toll like receptor (TLR) 4 has been reported to promote inflammation in diabetic nephropathy. However the role of TLR4 in the complicated pathophysiology of diabetic nephropathy is not understood. In this study, we report elevated expression of TLR4, its endogenous ligands and downstream cytokines, chemokines and fibrogenic genes in diabetic nephropathy in WT mice with streptozotocin (STZ) diabetes. Subsequently, we demonstrated that TLR4-/- mice were protected against the development of diabetic nephropathy, exhibiting less albuminuria, inflammation, glomerular hypertrophy and hypercellularity, podocyte and tubular injury as compared to diabetic wild-type controls. Marked reductions in interstitial collagen deposition, myofibroblast activation (α-SMA) and expression of fibrogenic genes (TGF-β and fibronectin) were also evident in TLR4 deficient mice. Consistent with our in vivo results, high glucose directly promoted TLR4 activation in podocytes and tubular epithelial cells in vitro, resulting in NF-κB activation and consequent inflammatory and fibrogenic responses. Our data indicate that TLR4 activation may promote inflammation, podocyte and tubular epithelial cell injury and interstitial fibrosis, suggesting TLR4 is a potential therapeutic target for diabetic nephropathy.

‘Weaving Love’ is Hong Kong’s first outdoor pavilion constructed using the constructional 3D metal printing through Wire Arc Additive Manufacturing (WAAM) technology, making a transformative milestone in the application of this emerging technology for large-scale construction in the region. This paper documents the entire process—from the concept and design to fabrication and construction—of the “Weaving Love” pavilion, a constructional 3D-printed metal structure situated at the New Immigration Headquarters of Hong Kong. The project demonstrates the seamless integration of advanced WAAM technology, innovative parametric design, and collaborative efforts among government, industry, and academia. By leveraging these advanced technologies, the project team has created a structure that is not only visually stunning but also environmentally friendly and cost-effective—achievements that would have been unattainable using conventional construction methods. The project achieved significant reductions in construction time, cost, and material waste while pushing the boundaries of architectural design and structural engineering. The structure is one of the largest 3D-printed steel structures in the Hong Kong region, designed in accordance with established codes of practice, just like conventional steel structures. This pioneering project successfully utilized WAAM technology to bring the innovative design of an artistic expression to fruition, incorporating advanced structural analysis methods, optimization techniques, and supplementary physical tests. This paper presents summarized project data and methodological frameworks for implementing WAAM technology in construction applications, thereby contributing to the advancement of WAAM technology in construction industry.

The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D. The incidence of type 1 diabetes is increasing, potentially implicating non-genetic factors. Here the authors conduct an epigenome-wide association study in disease-discordant twins and find increased DNA methylation variability at genes associated with immune cell metabolism and the cell cycle.

Chronic hyperglycemia is a major risk factor for glomerular or retinal microangiopathy and cardiovascular complications of type 1 diabetes (T1D). At the interface of genetics and environment, dynamic epigenetic changes associated with hyperglycemia may unravel some of the mechanisms contributing to these T1D complications. In this study, blood samples were collected from 112 young patients at T1D diagnosis and 3 years later in average. Whole genome-wide bisulfite sequencing was used to measure blood DNA methylation changes of about 28 million CpGs at single base resolution over this time. Chronic hyperglycemia was estimated every 3–4 months by HbA1c measurement. Linear regressions with adjustment to age, sex, treatment duration, blood proportions and batch effects were employed to characterize the relationships between the dynamic changes of DNA methylation and average HbA1c levels. We identified that longitudinal DNA methylation changes at 815 CpGs (with suggestive p-value threshold of 1e-4) were associated with average HbA1c. Most of them (> 98%) were located outside of the promoter regions and were enriched in CpG island shores and multiple immune cell type specific accessible chromatin regions. Among the 36 more strongly associated loci (p-value < 5e-6), 16 were harbouring genes or non-coding sequences involved in angiogenesis regulation, glomerular and retinal vascularization or development, or coronary disease. Our findings support the identification of new genomic sites where CpG methylation associated with hyperglycemia may contribute to long-term complications of T1D, shedding light on potential mechanisms for further exploration.

We have performed a genome-wide analysis of common genetic variation controlling differential expression of transcript isoforms in the CEU HapMap population using a comprehensive exon tiling microarray covering 17,897 genes. We detected 324 genes with significant associations between flanking SNPs and transcript levels. Of these, 39% reflected changes in whole gene expression and 55% reflected transcript isoform changes such as splicing variants (exon skipping, alternative splice site use, intron retention), differential 5′ UTR (initiation of transcription) use, and differential 3′ UTR (alternative polyadenylation) use. These results demonstrate that the regulatory effects of genetic variation in a normal human population are far more complex than previously observed. This extra layer of molecular diversity may account for natural phenotypic variation and disease susceptibility.

Cell fate and identity require timely activation of lineage-specific and concomitant repression of alternate-lineage genes. How this process is epigenetically encoded remains largely unknown. In skeletal muscle stem cells, the myogenic regulatory factors are well-established drivers of muscle gene activation but less is known about how non-muscle gene repression is achieved. Here, we show that the master epigenetic regulator, Repressor Element 1-Silencing Transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a key regulator of this process. We show that many non-lineage genes retain permissive chromatin state but are actively repressed by REST. Loss of functional REST in muscle stem cells and progenitors disrupts muscle specific epigenetic and transcriptional signatures, impairs differentiation, and triggers apoptosis in progenitor cells, leading to depletion of the stem cell pool. Consequently, REST-deficient skeletal muscle exhibits impaired regeneration and reduced myofiber growth postnatally. Collectively, our data suggests that REST plays a key role in safeguarding muscle stem cell identity by repressing multiple non-muscle lineage and developmentally regulated genes in adult mice. Here the authors show that REST/NRSF represses non-muscle lineage genes in muscle stem cells and progenitors, preserving their identity and differentiation capacity. Loss of REST disrupts gene silencing, impairs muscle regeneration, and leads to stem cell pool depletion.

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context. Additionally, we find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides insights into genomic brain regulation as a function of early-life experience. Early-life adversity is thought to increase the risk of psychopathology through epigenetic mechanisms. Here, the authors profile 6 histone marks, chromatin states and DNA methylation in the lateral amygdala in subjects with a history of early-life adversity.

Myofibers are the main components of skeletal muscle, which is the largest tissue in the body. Myofibers are highly adaptive and can be altered under different biological and disease conditions. Therefore, transcriptional and epigenetic studies on myofibers are crucial to discover how chromatin alterations occur in the skeletal muscle under different conditions. However, due to the heterogenous nature of skeletal muscle, studying myofibers in isolation proves to be a challenging task. Single-cell sequencing has permitted the study of the epigenome of isolated myonuclei. While this provides sequencing with high dimensionality, the sequencing depth is lacking, which makes comparisons between different biological conditions difficult. Here, we report the first implementation of single myofiber ATAC-Seq, which allows for the sequencing of an individual myofiber at a depth sufficient for peak calling and for comparative analysis of chromatin accessibility under various physiological and disease conditions. Application of this technique revealed significant differences in chromatin accessibility between resting and regenerating myofibers, as well as between myofibers from a mouse model of Duchenne Muscular Dystrophy (mdx) and wild-type (WT) counterparts. This technique can lead to a wide application in the identification of chromatin regulatory elements and epigenetic mechanisms in muscle fibers during development and in muscle-wasting diseases.