Ligand-dependent transcription by the nuclear receptor glucocorticoid receptor (GR) is mediated by interactions with coregulators. The role of these interactions in determining selective binding of ...GR to regulatory elements remains unclear. Recent findings indicate that a large fraction of genomic GR binding coincides with chromatin that is accessible prior to hormone treatment, suggesting that receptor binding is dictated by proteins that maintain chromatin in an open state. Combining DNaseI accessibility and chromatin immunoprecipitation with high-throughput sequencing, we identify the activator protein 1 (AP1) as a major partner for productive GR-chromatin interactions. AP1 is critical for GR-regulated transcription and recruitment to co-occupied regulatory elements, illustrating an extensive AP1-GR interaction network. Importantly, the maintenance of baseline chromatin accessibility facilitates GR recruitment and is dependent on AP1 binding. We propose a model in which the basal occupancy of transcription factors acts to prime chromatin and direct inducible transcription factors to select regions in the genome.
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► AP1 and GR binding are universally associated with open chromatin ► GR binding is substantially associated with AP1 occupancy ► AP1 binding maintains chromatin accessibility at regulatory elements genome-wide ► AP1 establishes genomic binding patterns for signal-dependent factors such as GR
The glucocorticoid receptor (GR), like other eukaryotic transcription factors, regulates gene expression by interacting with chromatinized DNA response elements. Photobleaching experiments in living ...cells indicate that receptors transiently interact with DNA on the time scale of seconds and predict that the response elements may be sparsely occupied on average. Here, we show that the binding of one receptor at the glucocorticoid response element (GRE) does not reduce the steady-state binding of another receptor variant to the same GRE. Mathematical simulations reproduce this noncompetitive state using short GR/GRE residency times and relatively long times between DNA binding events. At many genomic sites where GR binding causes increased chromatin accessibility, concurrent steady-state binding levels for the variant receptor are actually increased, a phenomenon termed assisted loading. Temporally sparse transcription factor-DNA interactions induce local chromatin reorganization, resulting in transient access for binding of secondary regulatory factors.
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► Many transcription factors exchange with response elements on a time scale of seconds ► Proteins with identical recognition sites fail to exhibit competitive binding in vivo ► Models support dynamic, temporally sparse, factor/response element interactions ► “Assisted loading” results from chromatin remodeling that creates transient access
Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium ...was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials.
To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival.
From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival.
Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies.
Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival.
From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range IQR, 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score-adjusted hazard ratio, 0.69 95% CI, 0.53-0.9, P = .006).
Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival.
clinicaltrials.gov Identifier: NCT01014286.
The incidence of primary cutaneous melanoma continues to increase each year. Melanoma accounts for the majority of skin cancer–related deaths, but treatment is usually curative following early ...detection of disease. In this American Academy of Dermatology clinical practice guideline, updated treatment recommendations are provided for patients with primary cutaneous melanoma (American Joint Committee on Cancer stages 0-IIC and pathologic stage III by virtue of a positive sentinel lymph node biopsy). Biopsy techniques for a lesion that is clinically suggestive of melanoma are reviewed, as are recommendations for the histopathologic interpretation of cutaneous melanoma. The use of laboratory, molecular, and imaging tests is examined in the initial work-up of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, recommendations for surgical margins and the concepts of staged excision (including Mohs micrographic surgery) and nonsurgical treatments for melanoma in situ, lentigo maligna type (including topical imiquimod and radiation therapy), are updated. The role of sentinel lymph node biopsy as a staging technique for cutaneous melanoma is described, with recommendations for its use in clinical practice. Finally, current data regarding pregnancy and melanoma, genetic testing for familial melanoma, and management of dermatologic toxicities related to novel targeted agents and immunotherapies for patients with advanced disease are summarized.
Livestock keepers in sub-Saharan Africa face a range of pressures, including climate change, land loss, restrictive policies, and population increase. Widespread adaptation in response can lead to ...the emergence of new, non-traditional typologies of livestock production. We sought to characterise livestock production systems in two administrative regions in northern Tanzania, an area undergoing rapid social, economic, and environmental change. Questionnaire and spatial data were collected from 404 livestock-keeping households in 21 villages in Arusha and Manyara Regions in 2016. Multiple factor analysis and hierarchical cluster analysis were used to classify households into livestock production systems based on household-level characteristics. Adversity-based indicators of vulnerability, including reports of hunger, illness, and livestock, land and crop losses were compared between production systems. Three distinct clusters emerged through this process. The ethnic, environmental and livestock management characteristics of households in each cluster broadly mapped onto traditional definitions of 'pastoral', 'agro-pastoral' and 'smallholder' livestock production in the study area, suggesting that this quantitative classification system is complementary to more qualitative classification methods. Our approach allowed us to demonstrate a diversity in typologies of livestock production at small spatial scales, with almost half of study villages comprising more than one production system. We also found indicators of change within livestock production systems, most notably the adoption of crop agriculture in the majority of pastoral households. System-level heterogeneities in vulnerability were evident, with agro-pastoral households most likely to report hunger and pastoral households most likely to report illness in people and livestock, and livestock losses. We demonstrate that livestock production systems can provide context for assessing household vulnerability in northern Tanzania. Policy initiatives to improve household and community well-being should recognise the continuing diversity of traditional livestock production systems in northern Tanzania, including the diversity that can exist at small spatial scales.
Development, differentiation and response to environmental stimuli are characterized by sequential changes in cellular state initiated by the de novo binding of regulated transcriptional factors to ...their cognate genomic sites. The mechanism whereby a given regulatory factor selects a limited number of in vivo targets from a myriad of potential genomic binding sites is undetermined. Here we show that up to 95% of de novo genomic binding by the glucocorticoid receptor, a paradigmatic ligand-activated transcription factor, is targeted to preexisting foci of accessible chromatin. Factor binding invariably potentiates chromatin accessibility. Cell-selective glucocorticoid receptor occupancy patterns appear to be comprehensively predetermined by cell-specific differences in baseline chromatin accessibility patterns, with secondary contributions from local sequence features. The results define a framework for understanding regulatory factor-genome interactions and provide a molecular basis for the tissue selectivity of steroid pharmaceuticals and other agents that intersect the living genome.
Combinatorial binding of transcription factors to regulatory DNA underpins gene regulation in all organisms. Genetic variation in regulatory regions has been connected with diseases and diverse ...phenotypic traits
, but it remains challenging to distinguish variants that affect regulatory function
. Genomic DNase I footprinting enables the quantitative, nucleotide-resolution delineation of sites of transcription factor occupancy within native chromatin
. However, only a small fraction of such sites have been precisely resolved on the human genome sequence
. Here, to enable comprehensive mapping of transcription factor footprints, we produced high-density DNase I cleavage maps from 243 human cell and tissue types and states and integrated these data to delineate about 4.5 million compact genomic elements that encode transcription factor occupancy at nucleotide resolution. We map the fine-scale structure within about 1.6 million DNase I-hypersensitive sites and show that the overwhelming majority are populated by well-spaced sites of single transcription factor-DNA interaction. Cell-context-dependent cis-regulation is chiefly executed by wholesale modulation of accessibility at regulatory DNA rather than by differential transcription factor occupancy within accessible elements. We also show that the enrichment of genetic variants associated with diseases or phenotypic traits in regulatory regions
is almost entirely attributable to variants within footprints, and that functional variants that affect transcription factor occupancy are nearly evenly partitioned between loss- and gain-of-function alleles. Unexpectedly, we find increased density of human genetic variation within transcription factor footprints, revealing an unappreciated driver of cis-regulatory evolution. Our results provide a framework for both global and nucleotide-precision analyses of gene regulatory mechanisms and functional genetic variation.
One explanation for why people engage in frightening fictional experiences is that these experiences can act as simulations of actual experiences from which individuals can gather information and ...model possible worlds. Conducted during the COVID-19 pandemic, this study (n = 310) tested whether past and current engagement with thematically relevant media fictions, including horror and pandemic films, was associated with greater preparedness for and psychological resilience toward the pandemic. Since morbid curiosity has previously been associated with horror media use during the COVID-19 pandemic, we also tested whether trait morbid curiosity was associated with pandemic preparedness and psychological resilience during the COVID-19 pandemic. We found that fans of horror films exhibited greater resilience during the pandemic and that fans of “prepper” genres (alien-invasion, apocalyptic, and zombie films) exhibited both greater resilience and preparedness. We also found that trait morbid curiosity was associated with positive resilience and interest in pandemic films during the pandemic. Taken together, these results are consistent with the hypothesis that exposure to frightening fictions allow audiences to practice effective coping strategies that can be beneficial in real-world situations.
•Fans of horror films exhibit less psychological distress during COVID-19.•Fans of “prepper” films reported being more prepared for the pandemic.•Morbidly curious people exhibit greater positive resilience during COVID-19.•Morbidly curious people are more interested in pandemic films during the pandemic.
By convention in individual personality assessment, scores on self-report questionnaires within ±.5 standard deviations of the mean score for that trait are considered "average," whereas scores ...outside that range are reported as "high" or "low" levels of the trait. To date, no one has examined how well this convention corresponds to perceptions of low, average, or high trait levels by acquaintances. The present study compares the accuracy of the conventional ±.5 SD cutting scores for low, average, and high trait levels with cutting scores derived from Optimal Data Analysis (ODA; Yarnold & Seltysik, 2005) for 160 participants who completed the IPIP-NEO-300 (Goldberg, 1999; Johnson, 2014) and were rated by acquaintances on the 30 facets and 5 domains of that instrument. In 32 of 35 comparisons, the ±.5 convention was found to be less accurate than the ODA method for deriving cutting scores.
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