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22
Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet.
, 2010
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Resource Genome-wide Chromatin State Transitions Associated with Developmental and Environmental Cues
"... Differences in chromatin organization are key to the multiplicity of cell states that arise from a single genetic background, yet the landscapes of in vivo tissues remain largely uncharted. Here, we mapped chromatin genome-wide in a large and diverse collection of human tissues and stem cells. The m ..."
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Differences in chromatin organization are key to the multiplicity of cell states that arise from a single genetic background, yet the landscapes of in vivo tissues remain largely uncharted. Here, we mapped chromatin genome-wide in a large and diverse collection of human tissues and stem cells. The maps yield unprecedented annotations of functional genomic elements and their regulation across developmental stages, lineages, and cellular environments. They also reveal global features of the epigenome, related to nuclear architecture, that also vary across cellular phenotypes. Specifically, developmental specification is accompanied by progressive chromatin restriction as the default state transitions from dynamic remodeling to generalized
VR: Allele-specific and heritable chromatin signatures in humans. Hum Mol Genet
, 2010
"... g.oxfordjournals.org/ D ow nloaded from 2 Next-generation sequencing based assays to detect gene regulatory elements are enabling the analysis of individual-to-individual and allele-specific variation of chromatin status and transcription factor binding in humans. Recently a number of studies have e ..."
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g.oxfordjournals.org/ D ow nloaded from 2 Next-generation sequencing based assays to detect gene regulatory elements are enabling the analysis of individual-to-individual and allele-specific variation of chromatin status and transcription factor binding in humans. Recently a number of studies have explored this area, using lymphoblastoid cell lines. Around 10 % of chromatin sites show either individual level differences or allele specific behavior. Future studies are likely to be limited by cell line accessibility, meaning that white blood cell based studies are likely to continue to be the main source of samples. A detailed understanding of the relationship between normal genetic variation and chromatin variation can shed light on how polymorphisms in non-coding regions in the human genome might underlie phenotypic variation and disease. at Pennsylvania State U niversity on Septem
Integration of Hi-C and ChIP-seq data reveals distinct types of chromatin linkages
, 2012
"... We have analyzed publicly available K562 Hi-C data, which enable genome-wide unbiased capturing of chromatin interactions, using a Mixture Poisson Regression Model and a power-law decay back-ground to define a highly specific set of interacting genomic regions. We integrated multiple ENCODE Consorti ..."
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Cited by 8 (0 self)
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We have analyzed publicly available K562 Hi-C data, which enable genome-wide unbiased capturing of chromatin interactions, using a Mixture Poisson Regression Model and a power-law decay back-ground to define a highly specific set of interacting genomic regions. We integrated multiple ENCODE Consortium resources with the Hi-C data, using DNase-seq data and ChIP-seq data for 45 transcrip-tion factors and 9 histone modifications. We classi-fied 12 different sets (clusters) of interacting loci that can be distinguished by their chromatin modi-fications and which can be categorized into two types of chromatin linkages. The different clusters of loci display very different relationships with
TCF7L2 is a master regulator of insulin production and processing. Human Molecular Genetics 23:6419e6431
, 2014
"... Genome-wide association studies have revealed>60 loci associated with type 2 diabetes (T2D), but the under-lying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet functi ..."
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Genome-wide association studies have revealed>60 loci associated with type 2 diabetes (T2D), but the under-lying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated tran-scriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors’, we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regu-lated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2D.
Transcription factor and chromatin features predict genes associated
, 2012
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DNA–protein interactions
, 2012
"... A multi-parametric flow cytometric assay to analyze ..."
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A multi-parametric flow cytometric assay to analyze
Evidence of non-pancreatic beta cell-dependent roles of Tcf7l2 in the regulation of glucose metabolism in mice. Human Molecular Genetics
, 2015
"... in the regulation of glucose metabolism in mice ..."
Ets homologous factor regulates pathways controlling response to injury in airway epithelial cells
, 2014
"... Ets homologous factor (EHF) is an Ets family tran-scription factor expressed in many epithelial cell types including those lining the respiratory system. Disruption of the airway epithelium is central to many lung diseases, and a network of transcription factors coordinates its normal function. EHF ..."
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Ets homologous factor (EHF) is an Ets family tran-scription factor expressed in many epithelial cell types including those lining the respiratory system. Disruption of the airway epithelium is central to many lung diseases, and a network of transcription factors coordinates its normal function. EHF can act as a transcriptional activator or a repressor, though its targets in lung epithelial cells are largely uncharac-terized. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq), showed that the major-ity of EHF binding sites in lung epithelial cells are intergenic or intronic and coincide with putative en-hancers, marked by specific histone modifications. EHF occupies many genomic sites that are close to genes involved in intercellular and cell–matrix adhe-sion. RNA-seq after EHF depletion or overexpression showed significant alterations in the expression of genes involved in response to wounding. EHF knock-down also targeted genes in pathways of epithe-lial development and differentiation and locomotory behavior. These changes in gene expression coin-cided with alterations in cellular phenotype includ-ing slowed wound closure and increased transep-ithelial resistance. Our data suggest that EHF regu-lates gene pathways critical for epithelial response to injury, including those involved in maintenance of barrier function, inflammation and efficient wound repair.
A multi-parametric flow cytometric assay to analyze DNA–protein interactions
, 2012
"... Interactions between DNA and transcription factors (TFs) guide cellular function anddevelopment, yet the complexitiesofgene regulationarestill far frombeing understood. Such understanding is limited by a paucity of techniques with which to probe DNA– protein interactions. We have devised magnetic pr ..."
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Interactions between DNA and transcription factors (TFs) guide cellular function anddevelopment, yet the complexitiesofgene regulationarestill far frombeing understood. Such understanding is limited by a paucity of techniques with which to probe DNA– protein interactions. We have devised magnetic protein immobilization on enhancer DNA (MagPIE), a simple, rapid, multi-parametric assay using flow cytometric immunofluorescence to reveal inter-actions among TFs, chromatin structure and DNA. In MagPIE, synthesized DNA is bound to magnetic beads, which are then incubated with nuclear lysate, permitting sequence-specific binding by TFs, histones andmethylation by native lysate factors that can be optionally inhibited with small molecules. Lysate protein–DNA binding is monitored by flow cytometric immunofluorescence, which allows for accurate comparative measurement of TF-DNA affinity. Combinatorial fluorescent staining allows simultaneous analysis of sequence-specific TF-DNA interaction and chromatin modification. MagPIE provides a simple and robust method to analyze complex epigenetic interactions in vitro.
