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"Hawkins, David"
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Candidate silencer elements for the human and mouse genomes
The study of gene regulation is dominated by a focus on the control of gene activation or increase in the level of expression. Just as critical is the process of gene repression or silencing. Chromatin signatures have identified enhancers, however, genome-wide identification of silencers by computational or experimental approaches are lacking. Here, we first define uncharacterized cis-regulatory elements likely containing silencers and find that 41.5% of ~7500 tested elements show silencer activity using massively parallel reporter assay (MPRA). We trained a support vector machine classifier based on MPRA data to predict candidate silencers in over 100 human and mouse cell or tissue types. The predicted candidate silencers exhibit characteristics expected of silencers. Leveraging promoter-capture HiC data, we find that over 50% of silencers are interacting with gene promoters having very low to no expression. Our results suggest a general strategy for genome-wide identification and characterization of silencer elements.
Journal Article
على طول الطريق نحو التنوير : 365 تأملا يوميا
ما الذي يعيق التقدم الروحاني ؟ وكيف نتجاوز هذه العقبات ؟ يعرف الطلاب الذين يسعون إلى إدراك الحقيقة الروحانية من جميع أنحاء العالم، التعاليم الروحانية لديفيد ر. هاوكينز التي تدور حول طبيعة الوعي والروح والأنا وبصفته فيلسوف وعالم روحاني، غرس الدكتور هاوكينز الحقائق الموجودة في تعاليم الدين الغربي بجوهر الفلسفة الشرقية، وربط العالم المادي المألوف بالمجال الروحاني غير الخطي تقدم هذه المجموعة من المقاطع المختارة بعناية من كتابات الدكتور هاوكينز الواسعة للقراء تأملا جديدا لكل يوم ويمكن لأي منها إذا ما فهم تماما أن يرفع من مستوى وعي الأفراد والمجتمع معا.
Book
Unsupervised Gait Event Identification with a Single Wearable Accelerometer and/or Gyroscope: A Comparison of Methods across Running Speeds, Surfaces, and Foot Strike Patterns
We evaluated 18 methods capable of identifying initial contact (IC) and terminal contact (TC) gait events during human running using data from a single wearable sensor on the shank or sacrum. We adapted or created code to automatically execute each method, then applied it to identify gait events from 74 runners across different foot strike angles, surfaces, and speeds. To quantify error, estimated gait events were compared to ground truth events from a time-synchronized force plate. Based on our findings, to identify gait events with a wearable on the shank, we recommend the Purcell or Fadillioglu method for IC (biases +17.4 and -24.3 ms; LOAs -96.8 to +131.6 and -137.0 to +88.4 ms) and the Purcell method for TC (bias +3.5 ms; LOAs -143.9 to +150.9 ms). To identify gait events with a wearable on the sacrum, we recommend the Auvinet or Reenalda method for IC (biases -30.4 and +29.0 ms; LOAs -149.2 to +88.5 and -83.3 to +141.3 ms) and the Auvinet method for TC (bias -2.8 ms; LOAs -152.7 to +147.2 ms). Finally, to identify the foot in contact with the ground when using a wearable on the sacrum, we recommend the Lee method (81.9% accuracy).
Journal Article
Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy
Gene replacement therapies utilizing adeno-associated viral (AAV) vectors hold great promise for treating Duchenne muscular dystrophy (DMD). A related approach uses AAV vectors to edit specific regions of the DMD gene using CRISPR/Cas9. Here we develop multiple approaches for editing the mutation in dystrophic mdx
mice using single and dual AAV vector delivery of a muscle-specific Cas9 cassette together with single-guide RNA cassettes and, in one approach, a dystrophin homology region to fully correct the mutation. Muscle-restricted Cas9 expression enables direct editing of the mutation, multi-exon deletion or complete gene correction via homologous recombination in myogenic cells. Treated muscles express dystrophin in up to 70% of the myogenic area and increased force generation following intramuscular delivery. Furthermore, systemic administration of the vectors results in widespread expression of dystrophin in both skeletal and cardiac muscles. Our results demonstrate that AAV-mediated muscle-specific gene editing has significant potential for therapy of neuromuscular disorders.
Journal Article
The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition
For nearly a century developmental biologists have recognized that cells from embryos can differ in their potential to differentiate into distinct cell types. Recently, it has been recognized that embryonic stem cells derived from both mice and humans exhibit two stable yet epigenetically distinct states of pluripotency: naive and primed. We now show that nicotinamide N-methyltransferase (NNMT) and the metabolic state regulate pluripotency in human embryonic stem cells (hESCs). Specifically, in naive hESCs, NNMT and its enzymatic product 1-methylnicotinamide are highly upregulated, and NNMT is required for low S-adenosyl methionine (SAM) levels and the H3K27me3 repressive state. NNMT consumes SAM in naive cells, making it unavailable for histone methylation that represses Wnt and activates the HIF pathway in primed hESCs. These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development.
Journal Article
Integrative analysis of 111 reference human epigenomes
The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
Journal Article