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Mapping human tissues with highly multiplexed RNA in situ hybridization
Application of multiplexed RNA in situ mapping techniques to human tissues remains challenging. Here, the authors report DART-FISH, a padlock probe-based technology capable of profiling large numbers of genes in centimetre-sized human tissue sections.
- Kian Kalhor
- , Chien-Ju Chen
- & Kun Zhang
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Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets
Genetic mechanisms of blood pressure regulation remain poorly defined. Here, the authors perform a kidney multi-omics study to identify 399 kidney effector genes, 11 miRNAs and 97 proteins for blood pressure and hypertension.
- Xiaoguang Xu
- , Chachrit Khunsriraksakul
- & Maciej Tomaszewski
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Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation
Here the authors report 20 novel genomic risk loci for calcific aortic valve stenosis, the most common heart valve disorder. Using RNA sequencing in 500 human aortic valves, they prioritize candidate causal genes including TWIST1, a gene involved in endothelial-mesenchymal transition.
- Sébastien Thériault
- , Zhonglin Li
- & Yohan Bossé
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YTHDF2 governs muscle size through a targeted modulation of proteostasis
This study highlights the role of YTHDF2, a protein that recognizes m6A-modified RNA, in determining muscle size. The authors show a post-transcriptional mechanism regulating muscle catabolism and growth, prompting interest to address muscle wasting.
- Christopher J. Gilbert
- , Charles P. Rabolli
- & Federica Accornero
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fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles
Extraocular muscles remain unaffected in muscular dystrophies. Here, the authors show that the gene fhl2b has a protective role in extraocular muscle and that its protective function can be applied to rescue other muscles in a zebrafish model of muscular dystrophy.
- Nils Dennhag
- , Abraha Kahsay
- & Fatima Pedrosa Domellöf
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Protein NirP1 regulates nitrite reductase and nitrite excretion in cyanobacteria
Some cyanobacteria excrete nitrite when the supply of inorganic carbon is limiting, but the underlying mechanisms are unclear. Here, Kraus et al. identify a conserved protein that interacts with nitrite reductase, thus regulating nitrogen metabolism and promoting nitrite excretion.
- Alexander Kraus
- , Philipp Spät
- & Wolfgang R. Hess
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A landscape of gene expression regulation for synovium in arthritis
Hundreds of arthritis-associated genetic variants have been identified but in most cases their functions remain unknown. Here the authors develop a resource to reveal the effects of variants on gene expression in human synovium, and identify arthritis-related genes.
- Feng Jiang
- , Shou-Ye Hu
- & Tie-Lin Yang
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Effect of aging on the human myometrium at single-cell resolution
Age-associated myometrial dysfunction can cause complications during pregnancy and labor. Here, the authors report that aging myometrium is characterized by diminished contractile capillary cells, altered gene expression, and disrupted cellular communication leading to impaired angiogenesis, increased fibrosis and inflammation.
- Paula Punzon-Jimenez
- , Alba Machado-Lopez
- & Aymara Mas
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GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region
Here, the authors identify six risk SNPs for systemic sclerosis by performing GWAS on Japanese patients and meta-analyzing Japanese and European GWAS datasets. Downstream analyses indicate that B cells contribute to pathogenesis.
- Yuki Ishikawa
- , Nao Tanaka
- & Chikashi Terao
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Transgenic expression of cif genes from Wolbachia strain wAlbB recapitulates cytoplasmic incompatibility in Aedes aegypti
The Wolbachia cifA and cifB genes generate cytoplasmic incompatibility (CI) in insect hosts but the role of cifA is still debated. Here, the authors report the transgenic recapitulation of CI in the major arbovirus vector Aedes aegypti and provide evidence for cifA inhibiting cifB toxicity in the male germline.
- Cameron J. McNamara
- , Thomas H. Ant
- & Steven P. Sinkins
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Haplotype-aware modeling of cis-regulatory effects highlights the gaps remaining in eQTL data
Genetic variants that influence gene expression play a major role in human phenotypic variability and disease susceptibility. Here, the authors introduce a computational method to estimate the regulatory effect size in genes with multiple conditionally independent regulatory variants.
- Nava Ehsan
- , Bence M. Kotis
- & Pejman Mohammadi
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A histone demethylase links the loss of plasticity to nongenetic inheritance and morphological change
A challenge for understanding plasticity is connecting macroevolutionary patterns to molecular mechanisms. Using a nematode model, this study identifies a mediator of nongenetic inheritance which is linked to multigenerational shifts in plasticity and morphology.
- Nicholas A. Levis
- & Erik J. Ragsdale
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STalign: Alignment of spatial transcriptomics data using diffeomorphic metric mapping
Spatial transcriptomics (ST) enables gene expression characterisation within tissue sections, but comparing across sections and technologies remains challenging. Here, authors develop STalign to spatially align ST data and demonstrate applications including aligning to common coordinate frameworks.
- Kalen Clifton
- , Manjari Anant
- & Jean Fan
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The SPOC proteins DIDO3 and PHF3 co-regulate gene expression and neuronal differentiation
Death-inducer obliterator 3 (DIDO3) and PHD finger protein 3 (PHF3) are paralogue proteins that regulate transcription elongation by docking onto phosphorylated serine-2 in the C-terminal domain (CTD) of Pol II through their SPOC domains. Here the authors characterize the interplay of these proteins and show that they coregulate neuronal target genes.
- Johannes Benedum
- , Vedran Franke
- & Dea Slade
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High-resolution temporal profiling of E. coli transcriptional response
Understanding how cells dynamically adapt to their environment is important, but temporal information about cellular behaviour is often limited. Here, Miano et al. apply unsupervised machine learning to a dataset describing the activity of over 1,800 promoters in E. coli, measured every 10 minutes, defining three primary stages of promoter activation in response to heavy metal stress.
- Arianna Miano
- , Kevin Rychel
- & Jeff Hasty
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Transcriptome-wide association analyses reveal the impact of regulatory variants on rice panicle architecture and causal gene regulatory networks
Panicle architecture significantly determines rice grain yield. Here, the authors investigate the transcriptome of young panicles from 275 rice varieties and propose a method to identify causal genes for panicle traits and construct regulatory networks.
- Luchang Ming
- , Debao Fu
- & Weibo Xie
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Hofbauer cell function in the term placenta associates with adult cardiovascular and depressive outcomes
Placental inflammation is sometimes associated with health outcomes later in life. Here, the authors find that expression of genes associated with the homeostatic function of Hofbauer cells, a placenta-specific macrophage, are associated with protection from adult cardiovascular and depressive disorders
- Eamon Fitzgerald
- , Mojun Shen
- & Michael J. Meaney
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The transcriptional legacy of developmental stochasticity
Minor perturbations or noise can significantly impact development but are difficult to assess. Here, the authors detail allelic expression imbalance across the development of nine-banded armadillos that indicate stochastic developmental canalization.
- Sara Ballouz
- , Risa Karakida Kawaguchi
- & Jesse Gillis
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Disrupting cellular memory to overcome drug resistance
Identifying memory and state switching in single cells remains elusive. Here, the authors develop a method, scMemorySeq, by combining cell barcoding and scRNA-seq and apply it to human melanoma cells to track lineages as they switch states between a drug-susceptible state and a state primed for drug resistance.
- Guillaume Harmange
- , Raúl A. Reyes Hueros
- & Sydney M. Shaffer
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Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia
Biallelic loss-of-function variants in the gene encoding Matrix Gla Protein (MGP) are known to cause a recessive disorder called Keutel syndrome. Here, the authors report that heterozygous missense variants affecting one particular cysteine residue of MGP can cause a clinically distinct, dominant disorder, likely via impaired signal peptide processing leading to cellular stress and apoptosis.
- Ophélie Gourgas
- , Gabrielle Lemire
- & Monzur Murshed
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PRO-IP-seq tracks molecular modifications of engaged Pol II complexes at nucleotide resolution
Tracking molecular modifications of engaged Pol II complexes is important for studying transcriptional regulation. Here, the authors combine run-on sequencing (PRO-seq) and immunoprecipitation, revealing dynamics of Pol II CTD phosphorylation at nucleotide-resolution.
- Anniina Vihervaara
- , Philip Versluis
- & John T. Lis
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Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis
Ferroptosis is a regulated form of cell death occurring upon lipid peroxidation. Here, the authors discovered that activation of the Farnesoid X receptor by bile acids suppresses ferroptosis through upregulation of anti-ferroptotic genes.
- Juliane Tschuck
- , Lea Theilacker
- & Kamyar Hadian
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A deep population reference panel of tandem repeat variation
Tandem repeats (TRs) comprise some of the most polymorphic regions of the human genome but are difficult to study. Here, the authors develop an ensemble-based genotyping method and characterize 1.7 million TRs across 3,550 humans from diverse populations.
- Helyaneh Ziaei Jam
- , Yang Li
- & Melissa Gymrek
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NeST: nested hierarchical structure identification in spatial transcriptomic data
A wide variety of tissues exhibit nested hierarchical organisation of cells in gene expression and activities. Here, authors present NeST, a method for spatial transcriptomics to identify such structures and uncover their functions via ligand-receptor communication, in both two and three dimensions.
- Benjamin L. Walker
- & Qing Nie
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Miniature spatial transcriptomics for studying parasite-endosymbiont relationships at the micro scale
The filarial worm Brugia malayi has evolved a mutualistic association with the endosymbiotic bacteria Wolbachia. Here, Sounart et al describe a spatial transcriptomic technique that can spatially resolve these miniature specimens.
- Hailey Sounart
- , Denis Voronin
- & Stefania Giacomello
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Benchmarking strategies for cross-species integration of single-cell RNA sequencing data
The growing number of available single-cell RNA-sequencing datasets from different species creates opportunities to explore evolutionary relationships between cell types across species. Here, the authors compare different strategies for cross-species integration of these data and offer guidelines for effective integration.
- Yuyao Song
- , Zhichao Miao
- & Irene Papatheodorou
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Single-cell allele-specific expression analysis reveals dynamic and cell-type-specific regulatory effects
Here the authors develop DAESC, a statistical method for differential allele-specific expression analysis using single-cell RNA-seq data. Application of DAESC identifies dynamic regulatory effects along endoderm differentiation and differential effects between type 2 diabetes and healthy controls.
- Guanghao Qi
- , Benjamin J. Strober
- & Alexis Battle
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Multifaceted analysis of cross-tissue transcriptomes reveals phenotype–endotype associations in atopic dermatitis
Atopic dermatitis is an inflammatory skin disease featuring systemic involvement. Here authors show that the two major clinical manifestations of the disease, erythema and papulation, are distinguished by differential interplay between local skin and systemic immunity, uncovered by integrated transcriptomics.
- Aiko Sekita
- , Hiroshi Kawasaki
- & Haruhiko Koseki
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C. elegans germ granules sculpt both germline and somatic RNAome
Germ granules are membraneless organelles that act as organizing centers for small RNA biogenesis during germline development. Here they show the LOTUS domain protein eggd-1 organizes germ granules, and reveal a germ line-to-soma communication pathway activated upon perturbation of germ granules.
- Ian F. Price
- , Jillian A. Wagner
- & Wen Tang
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A R-loop sensing pathway mediates the relocation of transcribed genes to nuclear pore complexes
Here the authors report that DNA:RNA hybrid-containing R-loop structures are sensed by the ssDNA-binding protein RPA, triggering their relocation to nuclear pore complexes and attenuating transcription-associated genetic instability.
- Arianna Penzo
- , Marion Dubarry
- & Benoit Palancade
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SHIELD: a platform for high-throughput screening of barrier-type DNA elements in human cells
Chromatin boundary elements are hard to define and characterize. Here the authors report Site-specific Heterochromatin Insertion of Elements at Lamina-associated Domains (SHIELD) for high-throughput screening of barrier-type DNA elements in human cells.
- Meng Zhang
- , Mary Elisabeth Ehmann
- & Huimin Zhao
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Projecting RNA measurements onto single cell atlases to extract cell type-specific expression profiles using scProjection
Many expression deconvolution approaches have been developed to estimate % RNA contributions of diverse cell types to mixed RNA measurements. Here, the authors have developed a complementary approach called scProjection to recover cell type-specific expression profiles from mixed RNA measurements.
- Nelson Johansen
- , Hongru Hu
- & Gerald Quon
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Cell-specific and shared regulatory elements control a multigene locus active in mammary and salivary glands
The authors investigate the regulatory complexity of a multigene locus with 20 candidate regulatory elements, including an ancestral super-enhancer, active in mammary and salivary tissue and local enhancers and promoter elements unique to mammary tissue.
- Hye Kyung Lee
- , Michaela Willi
- & Lothar Hennighausen
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Spatial transcriptomics reveal markers of histopathological changes in Duchenne muscular dystrophy mouse models
Duchenne muscular dystrophy is a fatal neuromuscular disorder affecting one in 5000 male births. To enrich our understanding of the underlying pathology, the authors apply spatial transcriptomics on dystrophic skeletal muscle to unravel markers related to histopathological changes in Duchenne mouse models.
- L.G.M. Heezen
- , T. Abdelaal
- & P. Spitali
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Integrative analysis of transcriptome dynamics during human craniofacial development identifies candidate disease genes
Craniofacial disorders are among the most common congenital defects. Here, the authors examined the genetic causes of non-syndromic craniofacial disorders during human development through analysis of gene expression and epigenomics.
- Tara N. Yankee
- , Sungryong Oh
- & Justin Cotney
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Modulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging
The extent of phosphorylated p38 MAPK is known to determine signaling. Here, the authors show the relative pool of non-phosphorylated p38 MAPK modulates signaling output to control growth, lysosome formation and neuronal integrity during early aging.
- Wang Yuan
- , Yi M. Weaver
- & Benjamin P. Weaver
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Increased body mass index is linked to systemic inflammation through altered chromatin co-accessibility in human preadipocytes
Preadipocytes contribute to the pro-inflammatory environment in obesity, via unknown mechanisms. Here, comparing monozygotic twin pairs, the authors show that co-accessibility of chromatin in preadipocytes is altered in siblings with higher compared to lower BMI, and that variants in these regions contribute to systemic inflammation via interactions with BMI.
- Kristina M. Garske
- , Asha Kar
- & Päivi Pajukanta
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Important role of endogenous microbial symbionts of fish gills in the challenging but highly biodiverse Amazonian blackwaters
Amazonian blackwaters are acidic and physiologically-challenging, but are one of Earth’s most diversified ecosystems. This study revealed that fish survival in these hostile habitats depends on the colonization of their gills by endogenous blackwater Betaproteobacteria, with the potential to regulate host ionoregulatory processes.
- Sylvain François-Étienne
- , Leroux Nicolas
- & Derome Nicolas
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UBAP2 plays a role in bone homeostasis through the regulation of osteoblastogenesis and osteoclastogenesis
The authors identify UBAP2 as a novel osteoporosis susceptibility gene by performing association studies focusing on coding regions of the genome, and report that it plays a role in bone homeostasis through the regulation of bone remodelling.
- Jeonghyun Kim
- , Bo-Young Kim
- & Seon-Yong Jeong
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A village in a dish model system for population-scale hiPSC studies
Village cultures, where multiple stem cell lines are cultured in a single dish, provide an elegant solution for population-scale studies. Here, authors show the utility of village models – showing that expression heterogeneity is largely a result of line-specific effects and not village cultures.
- Drew R. Neavin
- , Angela M. Steinmann
- & Joseph E. Powell
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Host transcriptomic plasticity and photosymbiotic fidelity underpin Pocillopora acclimatization across thermal regimes in the Pacific Ocean
Using data from the Tara Pacific expedition to investigate symbiont fidelity and patterns of gene expression across a thermal gradient, this study shows that Pocillopora corals have a three-tiered strategy of thermal acclimatization that is underpinned by host–photosymbiont specificity, host transcriptomic plasticity, and differential photosymbiotic associations under extreme warming.
- Eric J. Armstrong
- , Julie Lê-Hoang
- & Patrick Wincker
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A computational method for cell type-specific expression quantitative trait loci mapping using bulk RNA-seq data
Detecting cell type-specific genetic effects on gene expression is challenging in bulk RNA-seq data. Here, the authors develop a method to increase power which incorporates allele-specific expression and does not transform the gene expression data.
- Paul Little
- , Si Liu
- & Wei Sun
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Article
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Prioritization of potential causative genes for schizophrenia in placenta
The placenta has been proposed to be potentially relevant to schizophrenia risk. Here, the authors use the genetically predicted transcriptome to identify genes expressed in the placenta that could be involved in schizophrenia.
- Gianluca Ursini
- , Pasquale Di Carlo
- & Daniel R. Weinberger
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The NELF pausing checkpoint mediates the functional divergence of Cdk9
Promoter-proximal pausing by RNA Pol II is a key aspect of how gene expression is transcriptionally regulated in higher eukaryotes. Here the authors show that only NELF-mediated pausing enforces a strict early checkpoint for Cdk9 by efficiently shutting down gene transcription following loss of Cdk9.
- Michael DeBerardine
- , Gregory T. Booth
- & John T. Lis
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Cap analogs with a hydrophobic photocleavable tag enable facile purification of fully capped mRNA with various cap structures
Removing immunogenic uncapped mRNA from transcribed mRNA can be challenging, but is critical in mRNA research and clinical applications such as vaccines. Here, authors develop hydrophobic photocaged tag-modified cap analogs, which can be used to separate capped mRNA from uncapped mRNA, with subsequent tag removal using photo-irradiation.
- Masahito Inagaki
- , Naoko Abe
- & Hiroshi Abe
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meQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans
Here, the authors performed a large-scale in-depth cis-meQTL mapping study in 961 African Americans from the GENOA study, investigating the co-regulation of methylation and gene expression in African Americans.
- Lulu Shang
- , Wei Zhao
- & Xiang Zhou
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Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis
Transcriptional dysregulation contributes to tumor progression. Here the authors show that transcriptional complex NELF interacts with SLUG, and co-opts KAT2B, to promote the expression of epithelial-mesenchymal transition (EMT) and stemness-associated genes in breast cancer.
- Jieqiong Zhang
- , Zhenhua Hu
- & Wee-Wei Tee
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Article
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An interactive murine single-cell atlas of the lung responses to radiation injury
Radiation damages the healthy lung and triggers severe side effects. Here the authors provide a single cell atlas of the lung responses to radiation injury to explore the spatio-temporal dynamics of the mechanisms leading to radio-induced pulmonary fibrosis.
- Sandra Curras-Alonso
- , Juliette Soulier
- & Charles Fouillade
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Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation
Heterotopic ossification is a disorder characterized by the transformation of soft tissue to bone. In this study the authors report heterotopic ossification in a child caused by enhancer hijacking at the ARHGAP36 gene, the ectopic activation by an enhancer that it not its own.
- Uirá Souto Melo
- , Jerome Jatzlau
- & Malte Spielmann
A conserved NR5A1-responsive enhancer regulates SRY in testis-determination