Author Correction: An atlas of dynamic chromatin landscapes in mouse fetal development
Correction to: Nature https://doi.org/10.1038/s41586-020-2093-3 Published online 29 July 2020
59 BASIC BIOLOGICAL SCIENCES↗
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An atlas of dynamic chromatin landscapes in mouse fetal development
The Encyclopedia of DNA Elements (ENCODE) project has established a genomic resource for mammalian development, profiling a diverse panel of mouse tissues at 8 developmental stages from 10.5 days after conception until birth, including transcriptomes, methylomes and chromatin states. Here we systematically examined the state and accessibility of chromatin in the developing mouse fetus. In total we performed 1,128 chromatin immunoprecipitation with sequencing (ChIP–seq) assays for histone modifications and 132 assay for transposase-accessible chromatin using sequencing (ATAC–seq) assays for chromatin accessibility across 72 distinct tissue-stages. We used integrative analysis to develop a unified set of chromatin state annotations, infer the identities of dynamic enhancers and key transcriptional regulators, and characterize the relationship between chromatin state and accessibility during developmental gene regulation. We also leveraged these data to link enhancers to putative target genes and demonstrate tissue-specific enrichments of sequence variants associated with disease in humans. The mouse ENCODE data sets provide a compendium of resources for biomedical researchers and achieve, to our knowledge, the most comprehensive view of chromatin dynamics during mammalian fetal development to date.
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Perspectives on ENCODE
The Encyclopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression. The project has been extended to model organisms, particularly the mouse. Finally, in the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.
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Author Correction: An atlas of dynamic chromatin landscapes in mouse fetal development
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Author Correction: Perspectives on ENCODE
In the original article, the authors Rizi Ai (Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA) and Shantao Li (Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA) were mistakenly omitted from the ENCODE Project Consortium author list. The original Article has been corrected online.
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Author Correction: Expanded encyclopaedias of DNA elements in the human and mouse genomes
In the version of this article initially published, two members of the ENCODE Project Consortium were missing from the author list. Rizi Ai (Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA) and Shantao Li (Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA) are now included in the author list. These errors have been corrected in the online version of the article.
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Observation of quantum entanglement with top quarks at the ATLAS detector
Abstract Entanglement is a key feature of quantum mechanics 1–3 , with applications in fields such as metrology, cryptography, quantum information and quantum computation 4–8 . It has been observed in a wide variety of systems and length scales, ranging from the microscopic 9–13 to the macroscopic 14–16 . However, entanglement remains largely unexplored at the highest accessible energy scales. Here we report the highest-energy observation of entanglement, in top–antitop quark events produced at the Large Hadron Collider, using a proton–proton collision dataset with a centre-of-mass energy of √s = 13 TeV and an integrated luminosity of 140 inverse femtobarns (fb) −1 recorded with the ATLAS experiment. Spin entanglement is detected from the measurement of a single observableD, inferred from the angle between the charged leptons in their parent top- and antitop-quark rest frames. The observable is measured in a narrow interval around the top–antitop quark production threshold, at which the entanglement detection is expected to be significant. It is reported in a fiducial phase space defined with stable particles to minimize the uncertainties that stem from the limitations of the Monte Carlo event generators and the parton shower model in modelling top-quark pair production. The entanglement marker is measured to beD = −0.537 ± 0.002 (stat.) ± 0.019 (syst.) for$$340\,{\rm{GeV}} < {m}_{t\bar{t}} < 380\,{\rm{GeV}}$$ 340 GeV < m t t ¯ < 380 GeV . The observed result is more than five standard deviations from a scenario without entanglement and hence constitutes the first observation of entanglement in a pair of quarks and the highest-energy observation of entanglement so far.
Science & Technology - Other Topics↗
In vivo mapping of mutagenesis sensitivity of human enhancers
Distant-acting enhancers are central to human development1. However, our limited understanding of their functional sequence features prevents the interpretation of enhancer mutations in disease2. Here we determined the functional sensitivity to mutagenesis of human developmental enhancers in vivo. Focusing on seven enhancers that are active in the developing brain, heart, limb and face, we created over 1,700 transgenic mice for over 260 mutagenized enhancer alleles. Systematic mutation of 12-base-pair blocks collectively altered each sequence feature in each enhancer at least once. We show that 69% of all blocks are required for normal in vivo activity, with mutations more commonly resulting in loss (60%) than in gain (9%) of function. Using predictive modelling, we annotated critical nucleotides at the base-pair resolution. The vast majority of motifs predicted by these machine learning models (88%) coincided with changes in in vivo function, and the models showed considerable sensitivity, identifying 59% of all functional blocks. Taken together, our results reveal that human enhancers contain a high density of sequence features that are required for their normal in vivo function and provide a rich resource for further exploration of human enhancer logic.
Kosicki, Michael↗
Ultraconserved enhancer function does not require perfect sequence conservation
Ultraconserved enhancer sequences show perfect conservation between human and rodent genomes, suggesting that their functions are highly sensitive to mutation. However, current models of enhancer function do not sufficiently explain this extreme evolutionary constraint. We subjected 23 ultraconserved enhancers to different levels of mutagenesis, collectively introducing 1,547 mutations, and examined their activities in transgenic mouse reporter assays. Overall, we find that the regulatory properties of ultraconserved enhancers are robust to mutation. Upon mutagenesis, nearly all (19/23, 83%) still functioned as enhancers at one developmental stage, as did most of those tested again later in development (5/9, 56%). Replacement of endogenous enhancers with mutated alleles in mice corroborated results of transgenic assays, including the functional resilience of ultraconserved enhancers to mutation. Furthermore, our findings show that the currently known activities of ultraconserved enhancers do not necessarily require the perfect conservation observed in evolution and suggest that additional regulatory or other functions contribute to their sequence constraint.
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Supervised enhancer prediction with epigenetic pattern recognition and targeted validation
Enhancers are important non-coding elements, but they have traditionally been hard to characterize experimentally. The development of massively parallel assays allows the characterization of large numbers of enhancers for the first time. Here, we developed a framework using Drosophila STARR-seq to create shape-matching filters based on meta-profiles of epigenetic features. We integrated these features with supervised machine-learning algorithms to predict enhancers. We further demonstrated that our model could be transferred to predict enhancers in mammals. We comprehensively validated the predictions using a combination of in vivo and in vitro approaches, involving transgenic assays in mice and transduction-based reporter assays in human cell lines (153 enhancers in total). The results confirmed that our model can accurately predict enhancers in different species without re-parameterization. Finally, we examined the transcription factor binding patterns at predicted enhancers versus promoters. Here, we demonstrated that these patterns enable the construction of a secondary model that effectively distinguishes enhancers and promoters.
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Topologically associating domain boundaries are required for normal genome function
Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes1,2,3, but the overall extent to which this occurs remains unknown. Here we demonstrate that targeted deletions of TAD boundaries cause a range of disruptions to normal in vivo genome function and organismal development. We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11–80 kb in size) from the genome. All deletions examined resulted in detectable molecular or organismal phenotypes, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. We observed changes in local 3D chromatin architecture in 7 of 8 (88%) cases, including the merging of TADs and altered contact frequencies within TADs adjacent to the deleted boundary. For 5 of 8 (63%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to carefully consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening.
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SYMBA: An end-to-end VLBI synthetic data generation pipeline
Realistic synthetic observations of theoretical source models are essential for our understanding of real observational data. In using synthetic data, one can verify the extent to which source parameters can be recovered and evaluate how various data corruption effects can be calibrated. These studies are the most important when proposing observations of new sources, in the characterization of the capabilities of new or upgraded instruments, and when verifying model-based theoretical predictions in a direct comparison with observational data. We present the SYnthetic Measurement creator for long Baseline Arrays (SYMBA), a novel synthetic data generation pipeline for Very Long Baseline Interferometry (VLBI) observations. SYMBA takes into account several realistic atmospheric, instrumental, and calibration effects. Here, we used SYMBA to create synthetic observations for the Event Horizon Telescope (EHT), a millimetre VLBI array, which has recently captured the first image of a black hole shadow. After testing SYMBA with simple source and corruption models, we study the importance of including all corruption and calibration effects, compared to the addition of thermal noise only. Using synthetic data based on two example general relativistic magnetohydrodynamics (GRMHD) model images of M 87, we performed case studies to assess the image quality that can be obtained with the current and future EHT array for different weather conditions. Our synthetic observations show that the effects of atmospheric and instrumental corruptions on the measured visibilities are significant. Despite these effects, we demonstrate how the overall structure of our GRMHD source models can be recovered robustly with the EHT2017 array after performing calibration steps, which include fringe fitting, a priori amplitude and network calibration, and self-calibration. With the planned addition of new stations to the EHT array in the coming years, images could be reconstructed with higher angular resolution and dynamic range. In our case study, these improvements allowed for a distinction between a thermal and a non-thermal GRMHD model based on salient features in reconstructed images.
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Event Horizon Telescope imaging of the archetypal blazar 3C 279 at an extreme 20 microarcsecond resolution
3C 279 is an archetypal blazar with a prominent radio jet that show broadband flux density variability across the entire electromagnetic spectrum. We use an ultra-high angular resolution technique – global Very Long Baseline Interferometry (VLBI) at 1.3 mm (230 GHz) – to resolve the innermost jet of 3C 279 in order to study its fine-scale morphology close to the jet base where highly variable γ-ray emission is thought to originate, according to various models. The source was observed during four days in April 2017 with the Event Horizon Telescope at 230 GHz, including the phased Atacama Large Millimeter/submillimeter Array (ALMA), at an angular resolution of ∼20 μas (at a redshift of z = 0.536 this corresponds to ∼0.13 pc ∼ 1700 Schwarzschild radii with a black hole mass MBH = 8 × 108 M⊙). Imaging and model-fitting techniques were applied to the data to parameterize the fine-scale source structure and its variation. We find a multicomponent inner jet morphology with the northernmost component elongated perpendicular to the direction of the jet, as imaged at longer wavelengths. The elongated nuclear structure is consistent on all four observing days and across different imaging methods and model-fitting techniques, and therefore appears robust. Owing to its compactness and brightness, we associate the northern nuclear structure as the VLBI “core”. This morphology can be interpreted as either a broad resolved jet base or a spatially bent jet. We also find significant day-to-day variations in the closure phases, which appear most pronounced on the triangles with the longest baselines. Our analysis shows that this variation is related to a systematic change of the source structure. Two inner jet components move non-radially at apparent speeds of ∼15 c and ∼20 c (∼1.3 and ∼1.7 μas day−1, respectively), which more strongly supports the scenario of traveling shocks or instabilities in a bent, possibly rotating jet. The observed apparent speeds are also coincident with the 3C 279 large-scale jet kinematics observed at longer (cm) wavelengths, suggesting no significant jet acceleration between the 1.3 mm core and the outer jet. The intrinsic brightness temperature of the jet components are ≲1010 K, a magnitude or more lower than typical values seen at ≥7 mm wavelengths. The low brightness temperature and morphological complexity suggest that the core region of 3C 279 becomes optically thin at short (mm) wavelengths.Key words: galaxies: active / galaxies: jets / galaxies: individual: 3C 279 / techniques: interferometric⋆ The data are only available at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/cat/J/A+A/640/A69 and at https://eventhorizontelescope.org/for-astronomers/data⋆⋆ Deceased.
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The eROSITA Final Equatorial-Depth Survey (eFEDS)
Here, we investigate the physical properties – such as the stellar mass (M * ), star-formation rate, infrared (IR) luminosity (L IR ), X-ray luminosity (L X ), and hydrogen column density (N H ) – of mid-IR (MIR) galaxies and active galactic nuclei (AGN) at z < 4 in the 140 deg 2 field observed by eROSITA on SRG using the Performance-and-Verification-Phase program named the eROSITA Final Equatorial Depth Survey (eFEDS). By cross-matching the WISE 22 μm (W4)-detected sample and the eFEDS X-ray point-source catalog, we find that 692 extragalactic objects are detected by eROSITA. We have compiled a multiwavelength dataset extending from X-ray to far-IR wavelengths. We have also performed (i) an X-ray spectral analysis, (ii) spectral-energy-distribution fitting using X-CIGALE, (iii) 2D image-decomposition analysis using Subaru Hyper Suprime-Cam images, and (iv) optical spectral fitting with QSFit to investigate the AGN and host-galaxy properties. For 7088 WISE 22 μm objects that are undetected by eROSITA, we have performed an X-ray stacking analysis to examine the typical physical properties of these X-ray faint and probably obscured objects. We find that (i) 82% of the eFEDS–W4 sources are classified as X-ray AGN with log L X > 42 erg s –1 ; (ii) 67 and 24% of the objects have log(L IR /L ⊙ ) > 12 and 13, respectively; (iii) the relationship between L X and the 6 μm luminosity is consistent with that reported in previous works; and (iv) the relationship between the Eddington ratio and N H for the eFEDS–W4 sample and a comparison with a model prediction from a galaxy-merger simulation indicates that approximately 5.0% of the eFEDS–W4 sources in our sample are likely to be in an AGN-feedback phase, in which strong radiation pressure from the AGN blows out the surrounding material from the nuclear region. Thanks to the wide area coverage of eFEDS, we have been able to constrain the ranges of the physical properties of the WISE 22 μm-selected sample of AGNs at z < 4, providing a benchmark for forthcoming studies on a complete census of MIR galaxies selected from the full-depth eROSITA all-sky survey.
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XXL-HSC: An updated catalogue of high-redshift ( z ≥ 3.5) X-ray AGN in the XMM-XXL northern field
X-rays offer a reliable method to identify active galactic nuclei (AGNs). However, in the high-redshift Universe, X-ray AGNs are poorly sampled due to their relatively low space density and the small areas covered by X-ray surveys. In addition to wide-area X-ray surveys, it is important to have deep optical data in order to locate the optical counterparts and determine their redshifts. Here, in this work, we built a high-redshift (z ≥ 3.5) X-ray-selected AGN sample in the XMM-XXL northern field using the most updated [0.5–2 keV] catalogue along with a plethora of new spectroscopic and multi-wavelength catalogues, including the deep optical Subaru Hyper Suprime-Cam (HSC) data, reaching magnitude limits i ~ 26 mag. We selected all the spectroscopically confirmed AGN and complement this sample with high-redshift candidates that are HSC g- and r-band dropouts. To confirm the dropouts, we derived their photometric redshifts using spectral energy distribution techniques. We obtained a sample of 54 high-z sources (28 with spec-z), the largest in this field so far (almost three times larger than in previous studies), and we estimated the possible contamination and completeness. We calculated the number counts (log N-log S) in different redshift bins and compared our results with previous studies and models. We provide the strongest high-redshift AGN constraints yet at bright fluxes (f 0.5 – 2 keV > 10 –15 erg s –1 cm –2 ). The samples of z ≥ 3.5, z ≥ 4, and z ≥ 5 are in agreement with an exponential decline model similar to that witnessed at optical wavelengths. Our work emphasises the importance of using wide-area X-ray surveys with deep optical data to uncover high-redshift AGNs.
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eROSITA Final Equatorial-Depth Survey (eFEDS) eFEDS X-ray view of WERGS radio galaxies selected by the Subaru/HSC and VLA/FIRST survey
We constructed the eROSITA X-ray catalog of radio galaxies discovered by the WERGS survey, made by cross-matching the wide area Subaru/Hyper Suprime-Cam (HSC) optical survey and VLA/FIRST 1.4 GHz radio survey. We report finding 393 eROSITA detected radio galaxies in the 0.5-2 keV band in the eFEDS field covering 140 deg 2 . Thanks to the wide and medium depth eFEDS X-ray survey down to f 0.5 - 2 keV = 6.5 × 10 -15 erg s -1 cm -2 , the sample contains the rare and most X-ray luminous radio galaxies above the knee of the X-ray luminosity function, spanning 44 < log(L 0.5-2 keV (abs,corr) /erg s -1 ) < 46.5 at 1 < z < 4. The sample also contains the sources around and below the knee for the sources 41 < log(L 0.5-2 keV (abs,corr) /erg s -1 ) < 45 at z < 1. Based on the X-ray properties obtained by the spectral fitting, 37 sources show obscured active galactic nucleus (AGN) signatures with log(N H /cm -2 ) > 22. These obscured and radio AGN reside in 0.4 < z < 3.2, indicating that they are obscured counterparts of the radio-loud quasar, which were missed in the previous optical quasar surveys. By combining radio and X-ray luminosities, we also investigated the jet production efficiency η jet = η rad P jet /L AGN,bol by utilizing the jet power of P jet . We find that there are 14 sources with extremely high jet production efficiency at η jet ≈ 1. This high η jet value might be a result of the decreased radiation efficiency of η rad < 0.1, due to the low accretion rate for those sources, and/or of the boosting due to the decline of L AGN,bol by a factor of 10-100 by keeping P jet constant in the previous Myr, indicating the experience of the AGN feedback. Finally, inferring the BH masses from the stellar mass, we find that X-ray luminous sources show the excess of the radio emission with respect to the value estimated from the fundamental plane. This radio emission excess cannot be explained by the Doppler boosting alone, and therefore the disk–jet connection of X-ray luminous eFEDS-WERGS is fundamentally different from the conventional fundamental plane which mainly covers the low-accretion regime.
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The cosmic web of X-ray active galactic nuclei seen through the eROSITA Final Equatorial Depth Survey (eFEDS)
Which galaxies in the general population turn into active galactic nuclei (AGNs) is a keystone of galaxy formation and evolution. Thanks to SRG/eROSITA’s contiguous 140 square degree pilot survey field, we constructed a large, complete, and unbiased soft X-ray flux-limited (FX > 6.5 × 10 -15 erg s -1 cm -2 ) AGN sample at low redshift, 0.05 < z < 0.55. Two summary statistics, the clustering using spectra from SDSS-V and galaxy-galaxy lensing with imaging from HSC, are measured and interpreted with halo occupation distribution and abundance matching models. Both models successfully account for the observations. We obtain an exceptionally complete view of the AGN halo occupation distribution. The population of AGNs is broadly distributed among halos with a mean mass of 3.9 -2.4 +2.0 × 10 12 M ⊙ . This corresponds to a large-scale halo bias of b(z = 0.34) = 0.99 -0.10 +0.08 . The central occupation has a large transition parameter, σ log 10 (M) = 1.28 ± 0.2. The satellite occupation distribution is characterized by a shallow slope, α sat = 0.73 ± 0.38. We find that AGNs in satellites are rare, with f sat < 20%. Most soft X-ray-selected AGNs are hosted by central galaxies in their dark matter halo. A weak correlation between soft X-ray luminosity and large-scale halo bias is confirmed (3.3σ). We discuss the implications of environmental-dependent AGN triggering. This study paves the way toward fully charting, in the coming decade, the coevolution of X-ray AGNs, their host galaxies, and dark matter halos by combining eROSITA with SDSS-V, 4MOST, DESI, LSST, and Euclid data.
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The persistent shadow of the supermassive black hole of M 87. I. Observations, calibration, imaging, and analysis
In April 2019, the Event Horizon Telescope (EHT) Collaboration reported the first-ever event-horizon-scale images of a black hole, resolving the central compact radio source in the giant elliptical galaxy M 87. These images reveal a ring with a southerly brightness distribution and a diameter of ∼42 μas, consistent with the predicted size and shape of a shadow produced by the gravitationally lensed emission around a supermassive black hole. These results were obtained as part of the April 2017 EHT observation campaign, using a global very long baseline interferometric radio array operating at a wavelength of 1.3 mm. Here, we present results based on the second EHT observing campaign, taking place in April 2018 with an improved array, wider frequency coverage, and increased bandwidth. In particular, the additional baselines provided by the Greenland telescope improved the coverage of the array. Multiyear EHT observations provide independent snapshots of the horizon-scale emission, allowing us to confirm the persistence, size, and shape of the black hole shadow, and constrain the intrinsic structural variability of the accretion flow. We have confirmed the presence of an asymmetric ring structure, brighter in the southwest, with a median diameter of 43.3−3.1+1.5 μas. The diameter of the 2018 ring is remarkably consistent with the diameter obtained from the previous 2017 observations. On the other hand, the position angle of the brightness asymmetry in 2018 is shifted by about 30° relative to 2017. The perennial persistence of the ring and its diameter robustly support the interpretation that the ring is formed by lensed emission surrounding a Kerr black hole with a mass ∼6.5 × 109 M⊙. The significant change in the ring brightness asymmetry implies a spin axis that is more consistent with the position angle of the large-scale jet.
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