54 research outputs found
Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers
Background: Wilson disease (WD) is an autosomal recessive disease caused by mutations in ATP7B encoding a copper transporter. Consequent copper accumulation results in a variable WD clinical phenotype involving hepatic, neurologic, and psychiatric symptoms, without clear genotype–phenotype correlations. The goal of this study was to analyze alterations in DNA methylation at the whole-genome level in liver and blood from patients with WD to investigate epigenomic alterations associated with WD diagnosis and phenotype. We used whole-genome bisulfite sequencing (WGBS) to examine distinct cohorts of WD subjects to determine whether DNA methylation could differentiate patients from healthy subjects and subjects with other liver diseases and distinguish between different WD phenotypes.
Results: WGBS analyses in liver identified 969 hypermethylated and 871 hypomethylated differentially methylated regions (DMRs) specifically identifying patients with WD, including 18 regions with genome-wide significance. WD-specific liver DMRs were associated with genes enriched for functions in folate and lipid metabolism and acute inflammatory response and could differentiate early from advanced fibrosis in WD patients. Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2. DMRs associated with WD progression were also identified, including 15 with genome-wide significance. However, WD DMRs in liver were not related to large-scale changes in proportions of liver cell types. DMRs detected in blood differentiated WD patients from healthy and disease control subjects, and distinguished between patients with hepatic and neurologic WD manifestations. WD phenotype DMRs corresponded to genes enriched for functions in mental deterioration, abnormal B cell physiology, and as members of the polycomb repressive complex 1 (PRC1). 44 DMRs associated with WD phenotype tested in a small validation cohort had a predictive value of 0.9.
Conclusions: We identified a disease-mechanism relevant epigenomic signature of WD that reveals new insights into potential biomarkers and treatments for this complex monogenic disease
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A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood
Abstract
Background
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of children in the USA. ASD risk is thought to arise from both genetic and environmental factors, with the perinatal period as a critical window. Understanding early transcriptional changes in ASD would assist in clarifying disease pathogenesis and identifying biomarkers. However, little is known about umbilical cord blood gene expression profiles in babies later diagnosed with ASD compared to non-typically developing and non-ASD (Non-TD) or typically developing (TD) children.
Methods
Genome-wide transcript levels were measured by Affymetrix Human Gene 2.0 array in RNA from cord blood samples from both the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) and the Early Autism Risk Longitudinal Investigation (EARLI) high-risk pregnancy cohorts that enroll younger siblings of a child previously diagnosed with ASD. Younger siblings were diagnosed based on assessments at 36 months, and 59 ASD, 92 Non-TD, and 120 TD subjects were included. Using both differential expression analysis and weighted gene correlation network analysis, gene expression between ASD and TD, and between Non-TD and TD, was compared within each study and via meta-analysis.
Results
While cord blood gene expression differences comparing either ASD or Non-TD to TD did not reach genome-wide significance, 172 genes were nominally differentially expressed between ASD and TD cord blood (log2(fold change) > 0.1, p < 0.01). These genes were significantly enriched for functions in xenobiotic metabolism, chromatin regulation, and systemic lupus erythematosus (FDR q < 0.05). In contrast, 66 genes were nominally differentially expressed between Non-TD and TD, including 8 genes that were also differentially expressed in ASD. Gene coexpression modules were significantly correlated with demographic factors and cell type proportions.
Limitations
ASD-associated gene expression differences identified in this study are subtle, as cord blood is not the main affected tissue, it is composed of many cell types, and ASD is a heterogeneous disorder.
Conclusions
This is the first study to identify gene expression differences in cord blood specific to ASD through a meta-analysis across two prospective pregnancy cohorts. The enriched gene pathways support involvement of environmental, immune, and epigenetic mechanisms in ASD etiology.https://deepblue.lib.umich.edu/bitstream/2027.42/152245/1/13229_2019_Article_287.pd
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Using the Web to provide context: management development for 'sectors'
The Open University Business School (OUBS) is the major provider of distance learning based management education in Europe and is at the forefront of technological developments in this area. As a mass provider of management development, OUBS has had the problem of generating a standard assessed product together with opportunities to adapt or develop courses and programmes for discrete market segments with distinctive management development needs. In the 1980's and 1990's, OUBS met the needs of the voluntary and public sectors managers through the production of separate fixed component courses for voluntary and health and social service managers (Cornforth et al. 1998). At that time this approach was deemed necessary because of the fixed nature of the materials and the perceived gap between the commercial conceptions of management ideas and commonly accepted ideas about management in these sectors. Since then there has been a profound shift in thinking and managers in these sectors are more likely to wish to engage with a much wider range of management ideas drawing on commercial sector experience. This has made feasible the development of a single coherent curriculum. Within the Open University the course that has emerged, is on the leading edge of its development of teaching materials and is innovative in both pedagogy and technology.
This paper adds to knowledge about the contextualisation of management development for students from the Voluntary, Public and Health and Social Care sectors. It describes the rationale and practice for developing a new flexible course using the web and describes and evaluates our learning in adopting this approach to date. It outlines the underpinning philosophical and pedagogical ideas on which the approach is predicated and the main features of the learning experience. We explain the approach to versioning of material which includes a vision of a coherent curriculum for all managers whatever their context. This contextualises the material so that it appears directly relevant to their own experience. In part this stems from the reflective practitioner approach (Schon, 1984) which is inherent in our pedagogy. However, in our new course we have also pioneered making available additional contextual material using web technology.
All students enrolling on the course are required to be online and all communication is via e-mail and the Internet. In addition to face to face tutorials a significant element of the course is delivered online. This includes discussion around the preparation of assignments and the submission of assignments. For students from the Public and Nonprofit sectors they, in addition, have some versioned materials, a tutor who is from their context and a set of web-based context pages and conference areas. This paper focuses in particular on the challenges we have faced in developing and maintaining these online features and gives some initial assessment of student and tutor responses to the area. The paper will be illustrated by samples of the pages developed and show some of the pedagogical and technological challenges
Epigenetic changes of the thioredoxin system in the tx-j mouse model and in patients with Wilson disease.
Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers.
Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes.
Comethyl: a network-based methylome approach to investigate the multivariate nature of health and disease.
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