Estrogen-induced chromatin looping changes identify a subset of functional regulatory elements.

Transcriptional enhancers can regulate individual or multiple genes through long-range three-dimensional (3D) genome interactions, and these interactions are commonly altered in cancer. Yet, the functional relationship between changes in 3D interactions associated with regulatory regions and differential gene expression appears context-dependent. In this study, we used HiChiP to capture changes in 3D genome interactions between active regulatory regions of endometrial cancer cells in response to estrogen treatment and uncovered significant differential long-range interactions that are strongly enriched for estrogen receptor α (ER) bound sites (ERBS). The ERBS anchoring differential loops with either a gene's promoter or distal regions were correlated with larger transcriptional responses to estrogen compared to ERBS not involved in differential interactions. To functionally test this observation, CRISPR-based Enhancer-i was used to deactivate specific ERBS, which revealed a wide range of effects on the transcriptional response to estrogen. However, these effects are only subtly and not significantly stronger for ERBS in differential loops. In addition, we observed an enrichment of 3D interactions between the promoters of estrogen up-regulated genes and found that looped promoters can work together cooperatively. Overall, our work suggests that changes in 3D genome structure upon estrogen treatment identify some functionally important regulatory regions; however, these changes aren't required for a transcriptional response to E2 in endometrial cancer cells.

Cis-regulatory control of transcriptional timing and noise in response to estrogen.

Cis-regulatory elements control transcription levels, temporal dynamics, and cell-cell variation or transcriptional noise. However, the combination of regulatory features that control these different attributes is not fully understood. Here, we used single-cell RNA-seq during an estrogen treatment time course and machine learning to identify predictors of expression timing and noise. We found that genes with multiple active enhancers exhibit faster temporal responses. We verified this finding by showing that manipulation of enhancer activity changes the temporal response of estrogen target genes. Analysis of transcriptional noise uncovered a relationship between promoter and enhancer activity, with active promoters associated with low noise and active enhancers linked to high noise. Finally, we observed that co-expression across single cells is an emergent property associated with chromatin looping, timing, and noise. Overall, our results indicate a fundamental tradeoff between a gene's ability to quickly respond to incoming signals and maintain low variation across cells.

Cis-regulatory control of transcriptional timing and noise in response to estrogen.

Cis-regulatory elements control transcription levels, temporal dynamics, and cell-cell variation or transcriptional noise. However, the combination of regulatory features that control these different attributes is not fully understood. Here, we used single cell RNA-seq during an estrogen treatment time course and machine learning to identify predictors of expression timing and noise. We find that genes with multiple active enhancers exhibit faster temporal responses. We verified this finding by showing that manipulation of enhancer activity changes the temporal response of estrogen target genes. Analysis of transcriptional noise uncovered a relationship between promoter and enhancer activity, with active promoters associated with low noise and active enhancers linked to high noise. Finally, we observed that co-expression across single cells is an emergent property associated with chromatin looping, timing, and noise. Overall, our results indicate a fundamental tradeoff between a gene's ability to quickly respond to incoming signals and maintain low variation across cells.

Weighing up the evidence used by direct-to-consumer stem cell businesses.

Hundreds of businesses across the United States offer direct-to-consumer stem-cell-based interventions that have not been approved by the Food and Drug Administration. Here, we characterize the types of evidence used on the websites of 59 stem cell businesses in the Southwest United States to market their services. We identify over a dozen forms of evidence, noting that businesses are less likely to rely on "gold-standard" scientific evidence, like randomized clinical trials, and instead draw substantially on forms of evidence that we identify as being "ambiguous." Ambiguous evidence has some scientific or medical basis, but its interpretation is highly context-dependent. These findings highlight the interpretive responsibility placed on prospective patients. We identify actions for regulators and professional societies to assist with evaluating evidence, but caution that focusing on the (in)validity of particular evidence types is unlikely to eliminate demand for stem-cell-based treatments in this complex marketplace.

Water Storage Trends in High Mountain Asia.

Changes in terrestrial water storage (TWS) in High Mountain Asia (HMA) could have major societal impacts, as the region's large reservoirs of glaciers, snow, and groundwater provide a freshwater source to more than one billion people. We seek to quantify and close the budget of secular changes in TWS over the span of the GRACE satellite mission (2003-2016). To assess the TWS trend budget we consider a new high-resolution mass trend product determined directly from GRACE L1B data, glacier mass balance derived from Digital Elevation Models (DEMs), groundwater variability determined from confined and unconfined well observations, and terrestrial water budget estimates from a suite of land surface model simulations with the NASA Land Information System (LIS). This effort is successful at closing the aggregated TWS trend budget over the entire HMA region, the glaciated portion of HMA, and the Indus and Ganges basins, where the full-region trends are primarily due to the glacier mass balance and groundwater signals. Additionally, we investigate the closure of TWS trends at individual 1-arc-degree mascons (area ≈12,000 km2); a significant improvement in spatial resolution over previous analyses of GRACE-derived trends. This mascon-level analysis reveals locations where the TWS trends are well-explained by the independent datasets, as well as regions where they are not; identifying specific geographic areas where additional data and model improvements are needed. The accurate characterization of total TWS trends and its components presented here is critical to understanding the complex dynamics of the region, and is a necessary step toward projecting future water mass changes in HMA.

Evaluating the uncertainty of terrestrial water budget components over High Mountain Asia.

This study explores the uncertainties in terrestrial water budget estimation over High Mountain Asia (HMA) using a suite of uncoupled land surface model (LSM) simulations. The uncertainty in the water balance components of precipitation (P), evapotranspiration (ET), runoff(R), and terrestrial water storage (TWS) is significantly impacted by the uncertainty in the driving meteorology, with precipitation being the most important boundary condition. Ten gridded precipitation datasets along with a mix of model-, satellite-, and gauge-based products, are evaluated first to assess their suitability for LSM simulations over HMA. The datasets are evaluated by quantifying the systematic and random errors of these products as well as the temporal consistency of their trends. Though the broader spatial patterns of precipitation are generally well captured by the datasets, they differ significantly in their means and trends. In general, precipitation datasets that incorporate information from gauges are found to have higher accuracy with low Root Mean Square Errors and high correlation coefficient values. An ensemble of LSM simulations with selected subset of precipitation products is then used to produce the mean annual fluxes and their uncertainty over HMA in P, ET, and R to be 2.11±0.45, 1.26±0.11, and 0.85±0.36 mm per day, respectively. The mean annual estimates of the surface mass (water) balance components from this model ensemble are comparable to global estimates from prior studies. However, the uncertainty/spread of P, ET, and R is significantly larger than the corresponding estimates from global studies. A comparison of ET, snow cover fraction, and changes in TWS estimates against remote sensing-based references confirms the significant role of the input meteorology in influencing the water budget characterization over HMA and points to the need for improving meteorological inputs.

Uncertainty in global groundwater storage estimates in a Total Groundwater Stress framework.

Groundwater resilience is defined and quantified with remote sensing from GRACETimescales of aquifer depletion are assessed as a Total Groundwater Stress ratioThe volume of usable global groundwater storage is found to be largely unknown.

Quantifying renewable groundwater stress with GRACE.

Renewable groundwater stress is quantified in the world's largest aquifersCharacteristic stress regimes are defined to determine the severity of stressOverstressed aquifers are mainly in rangeland biomes with some croplands.