Direct GR Binding Sites Potentiate Clusters of TF Binding across the Human Genome

Vockley, Christopher M.; D’Ippolito, Anthony; McDowell, Ian C.; Majoros, William H.; Safi, Alexias; Song, Lingyun; Crawford, Gregory E.; Reddy, Timothy E.

doi:10.1016/j.cell.2016.07.049

Cited by 167 publications

(214 citation statements)

References 69 publications

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“…It has been known that GR binding sites with effects on expression are largely activating and highly enriched for the GR binding motif (Vockley et al 2016). Repressed enhancers, on the other hand, here had only subtle differences in GR binding from nondynamic enhancers.…”

Section: Discussionmentioning

confidence: 89%

“…Based on a recent finding that GR binding sites with GCinduced enhancer activity in a massively parallel reporter assay are strongly enriched for GR motifs (Vockley et al 2016), we hypothesized that the direct binding of GR, and also of other TFs, may explain the observed differences in changes in EP300 occupancy across enhancers. We first wanted to establish which motifs contributed to initial EP300 binding, prior to dex exposure.…”

Section: Cold Spring Harbor Laboratory Press On March 29 2019 -Publimentioning

confidence: 99%

“…Previous studies have shown that GR binding sites form local clusters in the genome, potentially via chromatin interactions between nearby enhancers (Kuznetsova et al 2015;Vockley et al 2016). GR binds to both pre-established chromatin loop anchors and induces novel chromatin interactions at sites with strong GR motifs (Kuznetsova et al 2015).…”

Section: Enhancer Dynamics Are Dependent Across Neighboring Enhancersmentioning

confidence: 99%

“…The trained model, which achieved high cross-validation accuracy (AUC = 0.80), benefitted from the integration of multiple epigenomic signals in a temporally and spatially aware manner (Supplemental Fig. S3H,I; Vockley et al 2016). …”

Section: Gcs Initiate a Cascade Of Genomic Eventsmentioning

confidence: 99%

“…Based on our observation that GC responses were highly coordinated across features, we reasoned that an integrated enhancer model that includes evidence from multiple assays and time points should enable the identification of dex-responsive enhancers. We trained a multivariate hidden Markov model (HMM) to classify dex-responsive enhancers as verified by a genome-scale high-throughput reporter assay (Arnold et al 2013;Vockley et al 2016). The trained model, which achieved high cross-validation accuracy (AUC = 0.80), benefitted from the integration of multiple epigenomic signals in a temporally and spatially aware manner (Supplemental Fig.…”

Section: Gcs Initiate a Cascade Of Genomic Eventsmentioning

confidence: 99%

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Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding

et al. 2018

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Glucocorticoids are potent steroid hormones that regulate immunity and metabolism by activating the transcription factor (TF) activity of glucocorticoid receptor (GR). Previous models have proposed that DNA binding motifs and sites of chromatin accessibility predetermine GR binding and activity. However, there are vast excesses of both features relative to the number of GR binding sites. Thus, these features alone are unlikely to account for the specificity of GR binding and activity. To identify genomic and epigenetic contributions to GR binding specificity and the downstream changes resultant from GR binding, we performed hundreds of genome-wide measurements of TF binding, epigenetic state, and gene expression across a 12-h time course of glucocorticoid exposure. We found that glucocorticoid treatment induces GR to bind to nearly all pre-established enhancers within minutes. However, GR binds to only a small fraction of the set of accessible sites that lack enhancer marks. Once GR is bound to enhancers, a combination of enhancer motif composition and interactions between enhancers then determines the strength and persistence of GR binding, which consequently correlates with dramatic shifts in enhancer activation. Over the course of several hours, highly coordinated changes in TF binding and histone modification occupancy occur specifically within enhancers, and these changes correlate with changes in the expression of nearby genes. Following GR binding, changes in the binding of other TFs precede changes in chromatin accessibility, suggesting that other TFs are also sensitive to genomic features beyond that of accessibility.

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Section: Discussionmentioning

confidence: 89%

Section: Cold Spring Harbor Laboratory Press On March 29 2019 -Publimentioning

confidence: 99%

Section: Enhancer Dynamics Are Dependent Across Neighboring Enhancersmentioning

confidence: 99%

Section: Gcs Initiate a Cascade Of Genomic Eventsmentioning

confidence: 99%

Section: Gcs Initiate a Cascade Of Genomic Eventsmentioning

confidence: 99%

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Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding

et al. 2018

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Optimizing the chances of success in the search for epigenetic biomarkers: Embracing genetic variation

Philibert

Glatt

2017

American J of Med Genetics Pt B

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The emphasis on clinical translation in biomedical research continues to grow. This focus has been particularly notable in those investigators using epigenetic approaches to decipher the biology of complex behavioral disorders. As a result of these efforts, reproducible findings for several disorders, such as smoking, have been generated, giving rise to hopes that biomarkers for other behavioral illnesses would be forthcoming. Unfortunately, that biomedical cornucopia has not yet materialized. In this editorial, we review progress to date and discuss barriers to generating epigenetic biomarkers for complex behavioral disorders. We highlight the need to incorporate information on genetic variation and develop more powerful bioinformatics tools in order to optimize the likelihood of success. We emphasize that searches should focus on clearly defined, readily distinguishable behavioral constructs and suggest that some well-intentioned methods, such as correction for cellular heterogeneity, may actually impede the identification of clinically relevant biomarkers in peripheral blood. Finally, we describe how the understanding created by the development of these biomarkers may lead to more valid animal models of neuropsychiatric illness. We conclude that the prospects for epigenetic biomarkers for complex disorders are bright, but emphasize that the journey to the clinical implementation of these findings will be a slow, iterative process.

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Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases

Bianchi,

Kozyrev,

Notarnicola

et al. 2024

Arthritis & Rheumatology

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OBJECTIVESSystemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study aimed at elucidating the genetics underlying these common features.METHODSWe performed targeted DNA sequencing of coding and regulatory regions from ~1,900 immune‐related genes in a large SIAD cohort of 2,292 well‐characterized Scandinavian patients with SLE, pSS and myositis, as well as 1,252 controls. A gene‐based functionally‐weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in‐silico functional analyses and in‐vitro reporter experiments.RESULTSCase‐control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case‐case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by ANA and anti‐dsDNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that DUSP1 protective genetic variants lead to increased gene expression and potentially to anti‐inflammatory effects on the SIAD‐associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported downregulation of the MAPK signaling‐related gene DUSP1 in other skin disorders.CONCLUSIONTogether, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.

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Direct GR Binding Sites Potentiate Clusters of TF Binding across the Human Genome

Cited by 167 publications

References 69 publications

Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding

Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding

Optimizing the chances of success in the search for epigenetic biomarkers: Embracing genetic variation

Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases

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