The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models.

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × âˆ¼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

GENCODE: reference annotation for the human and mouse genomes in 2023.

GENCODE produces high quality gene and transcript annotation for the human and mouse genomes. All GENCODE annotation is supported by experimental data and serves as a reference for genome biology and clinical genomics. The GENCODE consortium generates targeted experimental data, develops bioinformatic tools and carries out analyses that, along with externally produced data and methods, support the identification and annotation of transcript structures and the determination of their function. Here, we present an update on the annotation of human and mouse genes, including developments in the tools, data, analyses and major collaborations which underpin this progress. For example, we report the creation of a set of non-canonical ORFs identified in GENCODE transcripts, the LRGASP collaboration to assess the use of long transcriptomic data to build transcript models, the progress in collaborations with RefSeq and UniProt to increase convergence in the annotation of human and mouse protein-coding genes, the propagation of GENCODE across the human pan-genome and the development of new tools to support annotation of regulatory features by GENCODE. Our annotation is accessible via Ensembl, the UCSC Genome Browser and https://www.gencodegenes.org.

Photoswitchable Radical State in Nanoporous Metal-Organic Framework Films with Embedded Hexaarylbiimidazole.

Photoresponsive materials enable dynamic remote control of their fundamental properties. The incorporation of photochromic molecules in nanoporous metal-organic frameworks (MOFs) provides a unique opportunity to tailor the material properties, including the interaction between the MOF host and guest molecules in the pores. Here, a MOF film of type HKUST-1 with embedded hexaarylbiimidazole (HABI), undergoing reversible light-induced reactions between the stable dimer state and the metastable radical state, is presented. The switching between the dimer and radical form is shown by infrared, UV-vis, and electron paramagnetic resonance (EPR) spectroscopy. By transient uptake experiments with ethanol and methanol as probe molecules, we show that the dimer-radical switching impacts the host-guest interaction and, in particular, modifies the uptake amount and diffusion coefficient of the guest molecules. For ethanol, the diffusion slows down by 75%. This research presents the first MOF material with photoswitchable (meta)stable dimer and radical molecules, and it contributes to the advancement of photoresponsive nanoporous materials.

Nanoporous Films with Oriented Arrays of Molecular Motors for Photoswitching the Guest Adsorption and Diffusion.

Molecular motors are fascinating nanomachines. However, constructing smart materials from such functional molecules presents a severe challenge in material science. Here, we present a bottom-up layer-by-layer assembly of oriented overcrowded-alkene molecular motors forming a crystalline metal-organic framework thin film. While all stator parts of the overcrowded-alkene motors are oriented perpendicular to the substrate, the rotors point into the pores, which are large enough allowing for the light-induced molecular rotation. Taking advantage of the thin film's transparency, the motor rotation and its activation energy are determined by UV/Vis spectroscopy. As shown by gravimetric uptake experiments, molecular motors in crystalline porous materials are used, for the first time, to control the adsorption and diffusion properties of guest molecules in the pores, here, by switching with light between the (meta-)stable states. The work demonstrates the potential of designed materials with molecular motors and indicates a path for the future development of smart materials.

Substrate-Bound Diarylethene-Based Anisotropic Metal-Organic Framework Films as Photoactuators with a Directed Response.

Molecular machines and responsive materials open a plethora of new opportunities in nanotechnology. We present an oriented crystalline array of diarylethene (DAE)-based photoactuators, arranged in a way to yield an anisotropic response. The DAE units are assembled, together with a secondary linker, into a monolithic surface-mounted metal-organic framework (SURMOF) film. By Infrared (IR) and UV/Vis spectroscopy as well as by synchrotron X-ray diffraction, we show that the light-induced extension changes of the molecular DAE linkers multiply to yield mesoscopic and anisotropic length changes. Due to the special architecture and substrate-bonding of the SURMOF, these length changes are transferred to the macroscopic scale, leading to the bending of a cantilever and performing work. This research shows the potential of assembling light-powered molecules into SURMOFs to yield photoactuators with a directed response, presenting a path to advanced actuators.

Photoswitchable Metal-Organic Framework Thin Films: From Spectroscopy to Remote-Controllable Membrane Separation and Switchable Conduction.

The preparation of functional materials from photoswitchable molecules where the molecular changes multiply to macroscopic effects presents a great challenge in material science. An attractive approach is the incorporation of the photoswitches in nanoporous, crystalline metal-organic frameworks, MOFs, often showing remote-controllable chemical and physical properties. Because of the short light-penetration depth, thin MOF films are particularly interesting, allowing the entire illumination of the material. In the present progress report, we review and discuss the status of photoswitchable MOF films. These films may serve as model systems for quantifying the isomer switching yield by infrared and UV-vis spectroscopy as well as for uptake experiments exploring the switching effects on the host-guest interaction, especially on guest adsorption and diffusion. In addition, the straightforward device integration facilitates various experiments. In this way, unique features were demonstrated, such as photoswitchable membrane separation with continuously tunable selectivity, light-switchable proton conductivity of the guests in the pores, and remote-controllable electronic conduction.

Single-cell genomics and regulatory networks for 388 human brains.

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet, little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multi-omics datasets into a resource comprising >2.8M nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550K cell-type-specific regulatory elements and >1.4M single-cell expression-quantitative-trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

Single-cell genomics and regulatory networks for 388 human brains.

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

Optical sensor array of chiral MOF-based Fabry-Pérot films for enantioselective odor sensing.

An optical sensor array based on photonic Fabry-Pérot films of surface-mounted metal-organic-frameworks (SURMOFs) with different homochiral structures is presented. It is used to detect and enantioselectively discriminant 3 pairs of chiral odor molecules, either pure or in binary mixtures.

On-off conduction photoswitching in modelled spiropyran-based metal-organic frameworks.

Materials with photoswitchable electronic properties and conductance values that can be reversibly changed over many orders of magnitude are highly desirable. Metal-organic framework (MOF) films functionalized with photoresponsive spiropyran molecules demonstrated the general possibility to switch the conduction by light with potentially large on-off-ratios. However, the fabrication of MOF materials in a trial-and-error approach is cumbersome and would benefit significantly from in silico molecular design. Based on the previous proof-of-principle investigation, here, we design photoswitchable MOFs which incorporate spiropyran photoswitches at controlled positions with defined intermolecular distances and orientations. Using multiscale modelling and automated workflow protocols, four MOF candidates are characterized and their potential for photoswitching the conductivity is explored. Using ab initio calculations of the electronic coupling between the molecules in the MOF, we show that lattice distances and vibrational flexibility tremendously modulate the possible conduction photoswitching between spiropyran- and merocyanine-based MOFs upon light absorption, resulting in average on-off ratios higher than 530 and 4200 for p- and n-conduction switching, respectively. Further functionalization of the photoswitches with electron-donating/-withdrawing groups is demonstrated to shift the energy levels of the frontier orbitals, permitting a guided design of new spiropyran-based photoswitches towards controlled modification between electron and hole conduction in a MOF.

The ENCODE4 long-read RNA-seq collection reveals distinct classes of transcript structure diversity.

The majority of mammalian genes encode multiple transcript isoforms that result from differential promoter use, changes in exonic splicing, and alternative 3' end choice. Detecting and quantifying transcript isoforms across tissues, cell types, and species has been extremely challenging because transcripts are much longer than the short reads normally used for RNA-seq. By contrast, long-read RNA-seq (LR-RNA-seq) gives the complete structure of most transcripts. We sequenced 264 LR-RNA-seq PacBio libraries totaling over 1 billion circular consensus reads (CCS) for 81 unique human and mouse samples. We detect at least one full-length transcript from 87.7% of annotated human protein coding genes and a total of 200,000 full-length transcripts, 40% of which have novel exon junction chains. To capture and compute on the three sources of transcript structure diversity, we introduce a gene and transcript annotation framework that uses triplets representing the transcript start site, exon junction chain, and transcript end site of each transcript. Using triplets in a simplex representation demonstrates how promoter selection, splice pattern, and 3' processing are deployed across human tissues, with nearly half of multi-transcript protein coding genes showing a clear bias toward one of the three diversity mechanisms. Evaluated across samples, the predominantly expressed transcript changes for 74% of protein coding genes. In evolution, the human and mouse transcriptomes are globally similar in types of transcript structure diversity, yet among individual orthologous gene pairs, more than half (57.8%) show substantial differences in mechanism of diversification in matching tissues. This initial large-scale survey of human and mouse long-read transcriptomes provides a foundation for further analyses of alternative transcript usage, and is complemented by short-read and microRNA data on the same samples and by epigenome data elsewhere in the ENCODE4 collection.

EDTA-Functionalized Covalent Organic Framework for the Removal of Heavy-Metal Ions.

The removal of heavy-metal ions from wastewater has drawn intense attention, because of their toxicity, bioaccumulation tendency, and persistency in nature. Adsorption is regarded as one of the most promising methods, because of its simplicity and efficiency. In the present work, we report the preparation of a novel EDTA-functionalized covalent organic framework (COF) for the removal of heavy-metal ions. First, a COF named TpPa-NO2 was reduced to TpPa-NH2 by using Na2S2O4 as a reductant, and then EDTA dianhydride was grafted onto TpPa-NH2 to obtain TpPa-NH2@EDTA through post-modification. Both the COF morphology and structure remained unchanged after post-modification. The TpPa-NH2@EDTA showed excellent performance in adsorbing different types of heavy-metal ions, such as soft Lewis acid (Ag+, Pd2+), hard Lewis acid (Fe3+, Cr3+), and borderline Lewis acid (Cu2+, Ni2+), and the removal efficiencies are all >85% within 5 min, because of the strong chelation effect of EDTA. The TpPa-NH2@EDTA also showed high adsorption ability in a pH ≥3 environment and have an adsorption capacity of >50 mg/g for the six representative heavy-metal ions. This work provides a new idea for the application of COF materials in the removal of heavy-metal ions from wastewater.