Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the impact of human genetic variation on disease1-6. Here we create and evaluate a resource of >13 million enhancer-gene regulatory interactions across 352 cell types and tissues, by integrating predictive models, measurements of chromatin state and 3D contacts, and largescale genetic perturbations generated by the ENCODE Consortium7. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,411 elementgene pairs measured in CRISPR perturbation experiments, >30,000 fine-mapped eQTLs, and 569 fine-mapped GWAS variants linked to a likely causal gene. Using this framework, we develop a new predictive model, ENCODE-rE2G, that achieves state-of-the-art performance across multiple prediction tasks, demonstrating a strategy involving iterative perturbations and supervised machine learning to build increasingly accurate predictive models of enhancer regulation. Using the ENCODE-rE2G model, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, which reveals global properties of enhancer networks, identifies differences in the functions of genes that have more or less complex regulatory landscapes, and improves analyses to link noncoding variants to target genes and cell types for common, complex diseases. By interpreting the model, we find evidence that, beyond enhancer activity and 3D enhancer-promoter contacts, additional features guide enhancerpromoter communication including promoter class and enhancer-enhancer synergy. Altogether, these genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models, and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.

Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the impact of human genetic variation on disease1-6. Here we create and evaluate a resource of >13 million enhancer-gene regulatory interactions across 352 cell types and tissues, by integrating predictive models, measurements of chromatin state and 3D contacts, and large-scale genetic perturbations generated by the ENCODE Consortium7. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,411 element-gene pairs measured in CRISPR perturbation experiments, >30,000 fine-mapped eQTLs, and 569 fine-mapped GWAS variants linked to a likely causal gene. Using this framework, we develop a new predictive model, ENCODE-rE2G, that achieves state-of-the-art performance across multiple prediction tasks, demonstrating a strategy involving iterative perturbations and supervised machine learning to build increasingly accurate predictive models of enhancer regulation. Using the ENCODE-rE2G model, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, which reveals global properties of enhancer networks, identifies differences in the functions of genes that have more or less complex regulatory landscapes, and improves analyses to link noncoding variants to target genes and cell types for common, complex diseases. By interpreting the model, we find evidence that, beyond enhancer activity and 3D enhancer-promoter contacts, additional features guide enhancer-promoter communication including promoter class and enhancer-enhancer synergy. Altogether, these genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models, and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.

Hypothesis: Response of lipid bilayers to external mechanical stimuli is an active area of research with implications for fundamental and synthetic cell biology. Developing novel tools for systematically imposing mechanical strains and non-invasively mapping out interfacial (membrane) stress distributions on lipid bilayers can accelerate research in this field. Experiments: We report a miniature platform to manipulate model cell membranes in the form of droplet interface bilayers (DIBs), and non-invasively measure spatio-temporally resolved interfacial stresses using two photon fluorescence lifetime imaging of an interfacially active molecular flipper (Flipper-TR). We established the effectiveness of the developed framework by investigating interfacial stresses accompanying three key processes associated with DIBs: thin film drainage between lipid monolayer coated droplets, bilayer formation, and bilayer separation. Findings: The measurements revealed fundamental aspects of DIBs including the existence of a radially decaying interfacial stress distribution post bilayer formation, and the simultaneous build up and decay of stress respectively at the bilayer corner and center during bilayer separation. Finally, utilizing interfacial rheology measurements and MD simulations, we also reveal that the tested molecular flipper is sensitive to membrane fluidity that changes with interfacial stress expanding the scientific understanding of how molecular flippers sense stress.

Superpuffs are planets with exceptionally low densities (rho less than or similar to 0.1 g cm-3) and core masses (M c less than or similar to 5M circle plus). Many lower-mass (M p less than or similar to 10M circle plus) superpuffs are expected to be unstable to catastrophic mass loss via photoevaporation and/or boil-off, whereas the larger gravitational potentials of higher-mass (M p greater than or similar to 10M circle plus) superpuffs should make them more stable to these processes. We test this expectation by studying atmospheric loss in the warm, higher-mass superpuff TOI-1420b (M = 25.1M circle plus, R = 11.9R circle plus, rho = 0.08 g cm-3, T eq = 960 K). We observed one full transit and one partial transit of this planet using the metastable helium filter on Palomar/WIRC and found that the helium transits were 0.671% +/- 0.079% (8.5 sigma) deeper than the TESS transits, indicating an outflowing atmosphere. We modeled the excess helium absorption using a self-consistent 1D hydrodynamics code to constrain the thermal structure of the outflow given different assumptions for the stellar XUV spectrum. These calculations then informed a 3D simulation, which provided a good match to the observations with a modest planetary mass-loss rate of 1010.82 g s-1 ( M p / M approximate to 70 Gyr). Superpuffs with M p greater than or similar to 10M circle plus, like TOI-1420b and WASP-107b, appear perfectly capable of retaining atmospheres over long timescales; therefore, these planets may have formed with the unusually large envelope mass fractions they appear to possess today. Alternatively, tidal circularization could have plausibly heated and inflated these planets, which would bring their envelope mass fractions into better agreement with expectations from core-nucleated accretion.