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الماء مرآة العلم
إن الموضوع المركزي لكتاب الماء مرآة العلم، إن أردنا صياغة أخرى، لا يتضمن الماء بوصفه (حقيقة فيزيائية) فقط بل بوصفه (فكرة علمية) أيضا وبتطوير هذا الجانب الأخير يصبح موضوعنا الجوهري الذي سوف نعالجه هو (العلم) بحد ذاته، أي (العلم) باعتباره إنسانيا وتعبيرا عن الروح الإنسانية وأسلوبا لفهم العالم الطبيعي والتعامل معه.
Book
STAT3-mediated allelic imbalance of novel genetic variant Rs1047643 and B-cell-specific super-enhancer in association with systemic lupus erythematosus
Mapping of allelic imbalance (AI) at heterozygous loci has the potential to establish links between genetic risk for disease and biological function. Leveraging multi-omics data for AI analysis and functional annotation, we discovered a novel functional risk variant rs1047643 at 8p23 in association with systemic lupus erythematosus (SLE). This variant displays dynamic AI of chromatin accessibility and allelic expression on FDFT1 gene in B cells with SLE. We further found a B-cell restricted super-enhancer (SE) that physically contacts with this SNP-residing locus, an interaction that also appears specifically in B cells. Quantitative analysis of chromatin accessibility and DNA methylation profiles further demonstrated that the SE exhibits aberrant activity in B cell development with SLE. Functional studies identified that STAT3, a master factor associated with autoimmune diseases, directly regulates both the AI of risk variant and the activity of SE in cultured B cells. Our study reveals that STAT3-mediated SE activity and cis-regulatory effects of SNP rs1047643 at 8p23 locus are associated with B cell deregulation in SLE.
Journal Article
Stage-specific epigenetic regulation of CD4 expression by coordinated enhancer elements during T cell development
The inheritance of gene expression patterns is dependent on epigenetic regulation, but the establishment and maintenance of epigenetic landscapes during T cell differentiation are incompletely understood. Here we show that two stage-specific
Cd4 cis
-elements, the previously characterized enhancer E4p and a novel enhancer E4m, coordinately promote
Cd4
transcription in mature thymic MHC-II-specific T cells, in part through the canonical Wnt pathway. Specifically, E4p licenses E4m to orchestrate DNA demethylation by TET1 and TET3, which in turn poises the
Cd4
locus for transcription in peripheral T cells.
Cd4
locus demethylation is important for subsequent
Cd4
transcription in activated peripheral T cells wherein these
cis
-elements become dispensable. By contrast, in developing thymocytes the loss of TET1/3 does not affect
Cd4
transcription, highlighting an uncoupled event between transcription and epigenetic modifications. Together our findings reveal an important function for thymic
cis-
elements in governing gene expression in the periphery via a heritable epigenetic mechanism.
The expression of CD4, a critical co-receptor providing T cell help in adaptive immunity, is finely tuned during development. Here the authors show that two enhancer elements, E4p and the newly-defined E4m, coordinate the expression and heritable demethylation of
Cd4
in thymocytes but are dispensable for its sustained expression in peripheral T cells.
Journal Article
An Index of Summer Rainfall for Queensland’s Grazing Lands
A historical rainfall index, relevant to the grazing industries of Queensland, Australia, is described. We refer to our index as the Queensland grazing lands rainfall index (QGLRI), which is a long-term (1890/91–present) time series of austral summer (November–March) rainfall, spatially averaged over a region we define as the Queensland grazing lands region. We argue that our QGLRI better represents historical summer rainfall variability faced by the majority of the grazing industry in Queensland than does area-averaged statewide rainfall. The geographical boundaries of our region were chosen to 1) better represent the spatial patterns of land use, settlement, and livestock densities and 2) coincide with spatial patterns of airmass dominance. The selected region covers 59% of Queensland’s mainland area but carries more than 80% of the state’s livestock. The region’s boundaries also closely match the mean summer location of the boundaries of the “tropical maritime Pacific” air mass. The selected 5-month season (November–March) was chosen based on summer rainfall dominance, seasonal climatic effects restricting pasture and animal growth, and pasture management implications such as burning and the risk of overgrazing. We find that this season also corresponds to the timing of tropical maritime airmass dominance. The remaining regions of Queensland, far-northern and far-western Queensland, also correspond to well-defined dominant air masses, with properties that are markedly different from those of the tropical maritime Pacific air mass. We demonstrate that the rainfall regime in far-northern Queensland makes a strong contribution to statewide totals, resulting in statewide summer rainfall having lower variability than our QGLRI.
Journal Article
Injured inflammatory environment overrides the TET2 shaped epigenetic landscape of pluripotent stem cell derived human neural stem cells
Spinal cord injury creates an inflammatory microenvironment that regulates the capacity of transplanted human Neural Stem Cells (hNSC) to migrate, differentiate, and repair injury. Despite similarities in gene expression and markers detected by immunostaining, hNSC populations exhibit heterogeneous therapeutic potential. This heterogeneity derives in part from the epigenetic landscape in the hNSC genome, specifically methylation (5mC) and hydroxymethylation (5hmC) state, which may affect the response of transplanted hNSC in the injury microenvironment and thereby modulate repair capacity. We demonstrate a significant up-regulation of methylcytosine dioxygenase 2 gene (
TET2
) expression in undifferentiated hNSC derived from human embryonic stem cells (hES-NSC), and report that this is associated with hES-NSC competence for differentiation marker expression. TET2 protein catalyzes active demethylation and
TET2
upregulation could be a signature of pluripotent exit, while shaping the epigenetic landscape in hES-NSC. We determine that the inflammatory environment overrides epigenetic programming in vitro and in vivo by directly modulating
TET2
expression levels in hES-NSC to change cell fate. We also report the effect of cell fate and microenvironment on differential methylation 5mC/5hmC balance. Understanding how the activity of epigenetic modifiers changes within the transplantation niche in vivo is crucial for assessment of hES-NSC behavior for potential clinical applications.
Journal Article
dCATCH-Seq: improved sequencing of large continuous genomic targets with double-hybridization
Background
Targeted sequencing is a powerful tool with broad application in both basic and translational sciences. Relatively low on-target rates for most current targeted sequencing studies influence the required coverage and data quality for subsequent applications.
Results
We present an improved targeted sequencing method that uses two rounds of in solution hybridization with probes synthesized from genomic clone templates, termed dCATCH-Seq. Independent captures of two large continuous genomic regions across three cell types within the human major histocompatibility complex (MHC) that spans ~3.5 Mb and a ~250 kb region on chromosome 11 demonstrated that dCATCH-Seq was highly reproducible with ~95% capture specificity. Comprehensive analyses of sequencing data generated using the dCATCH-Seq approach also showed high accuracy in the detection of genetic variants and HLA typing. The double hybridization capture approach can also be coupled with bisulfite sequencing for DNA methylation profiling of both CpG and non-CpG sites.
Conclusions
Altogether, dCATCH-Seq is a powerful and scalable targeted sequencing approach to investigate both genetic and epigenetic features.
Journal Article
CD4 expression in effector T cells depends on DNA demethylation over a developmentally established stimulus-responsive element
The epigenetic patterns that are established during early thymic development might determine mature T cell physiology and function, but the molecular basis and topography of the genetic elements involved are not fully known. Here we show, using the
Cd4
locus as a paradigm for early developmental programming, that DNA demethylation during thymic development licenses a novel stimulus-responsive element that is critical for the maintenance of
Cd4
gene expression in effector T cells. We document the importance of maintaining high CD4 expression during parasitic infection and show that by driving transcription, this stimulus-responsive element allows for the maintenance of histone H3K4me3 levels during T cell replication, which is critical for preventing de novo DNA methylation at the
Cd4
promoter. A failure to undergo epigenetic programming during development leads to gene silencing during effector T cell replication. Our study thus provides evidence of early developmental events shaping the functional fitness of mature effector T cells.
Epigenetic states that are established during thymic T cell development influence functionality of mature T cells. Authors here show that early developmental programming of the
Cd4
locus is comprised of DNA-demethylation at a specific stimulus-responsive element, which allows long-term maintenance of activator histone H3K4 trimethylation and transcription.
Journal Article
Targeted Sequencing of Large Genomic Regions with CATCH-Seq
Current target enrichment systems for large-scale next-generation sequencing typically require synthetic oligonucleotides used as capture reagents to isolate sequences of interest. The majority of target enrichment reagents are focused on gene coding regions or promoters en masse. Here we introduce development of a customizable targeted capture system using biotinylated RNA probe baits transcribed from sheared bacterial artificial chromosome clone templates that enables capture of large, contiguous blocks of the genome for sequencing applications. This clone adapted template capture hybridization sequencing (CATCH-Seq) procedure can be used to capture both coding and non-coding regions of a gene, and resolve the boundaries of copy number variations within a genomic target site. Furthermore, libraries constructed with methylated adapters prior to solution hybridization also enable targeted bisulfite sequencing. We applied CATCH-Seq to diverse targets ranging in size from 125 kb to 3.5 Mb. Our approach provides a simple and cost effective alternative to other capture platforms because of template-based, enzymatic probe synthesis and the lack of oligonucleotide design costs. Given its similarity in procedure, CATCH-Seq can also be performed in parallel with commercial systems.
Journal Article
Recurrent Evolution of Melanism in South American Felids
Morphological variation in natural populations is a genomic test bed for studying the interface between molecular evolution and population genetics, but some of the most interesting questions involve non-model organisms that lack well annotated reference genomes. Many felid species exhibit polymorphism for melanism but the relative roles played by genetic drift, natural selection, and interspecies hybridization remain uncertain. We identify mutations of Agouti signaling protein (ASIP) or the Melanocortin 1 receptor (MC1R) as independent causes of melanism in three closely related South American species: the pampas cat (Leopardus colocolo), the kodkod (Leopardus guigna), and Geoffroy's cat (Leopardus geoffroyi). To assess population level variation in the regions surrounding the causative mutations we apply genomic resources from the domestic cat to carry out clone-based capture and targeted resequencing of 299 kb and 251 kb segments that contain ASIP and MC1R, respectively, from 54 individuals (13-21 per species), achieving enrichment of ~500-2500-fold and ~150x coverage. Our analysis points to unique evolutionary histories for each of the three species, with a strong selective sweep in the pampas cat, a distinctive but short melanism-specific haplotype in the Geoffroy's cat, and reduced nucleotide diversity for both ancestral and melanism-bearing chromosomes in the kodkod. These results reveal an important role for natural selection in a trait of longstanding interest to ecologists, geneticists, and the lay community, and provide a platform for comparative studies of morphological variation in other natural populations.
Journal Article
PEA15 loss of function and defective cerebral development in the domestic cat
Cerebral cortical size and organization are critical features of neurodevelopment and human evolution, for which genetic investigation in model organisms can provide insight into developmental mechanisms and the causes of cerebral malformations. However, some abnormalities in cerebral cortical proliferation and folding are challenging to study in laboratory mice due to the absence of gyri and sulci in rodents. We report an autosomal recessive allele in domestic cats associated with impaired cerebral cortical expansion and folding, giving rise to a smooth, lissencephalic brain, and that appears to be caused by homozygosity for a frameshift in PEA15 (phosphoprotein expressed in astrocytes-15). Notably, previous studies of a Pea15 targeted mutation in mice did not reveal structural brain abnormalities. Affected cats, however, present with a non-progressive hypermetric gait and tremors, develop dissociative behavioral defects and aggression with age, and exhibit profound malformation of the cerebrum, with a 45% average decrease in overall brain weight, and reduction or absence of the ectosylvian, sylvian and anterior cingulate gyrus. Histologically, the cerebral cortical layers are disorganized, there is substantial loss of white matter in tracts such as the corona radiata and internal capsule, but the cerebellum is relatively spared. RNA-seq and immunohistochemical analysis reveal astrocytosis. Fibroblasts cultured from affected cats exhibit increased TNFα-mediated apoptosis, and increased FGFb-induced proliferation, consistent with previous studies implicating PEA15 as an intracellular adapter protein, and suggesting an underlying pathophysiology in which increased death of neurons accompanied by increased proliferation of astrocytes gives rise to abnormal organization of neuronal layers and loss of white matter. Taken together, our work points to a new role for PEA15 in development of a complex cerebral cortex that is only apparent in gyrencephalic species.
Journal Article