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| Open AccessGWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements
Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.
- Peter H. Dixon
- , Adam P. Levine
- & Catherine Williamson
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Article
| Open AccessA reference single-cell regulomic and transcriptomic map of cynomolgus monkeys
Non-human primates are attractive laboratory animal models that can accurately reflect some developmental and pathological features of humans. Here the authors chart a reference cell map of cynomolgus monkeys using both scATAC-seq and scRNA-seq data across multiple organs, providing insights into the molecular dynamics and cellular heterogeneity of this organism.
- Jiao Qu
- , Fa Yang
- & Dijun Chen
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Article
| Open AccessChIP-Hub provides an integrative platform for exploring plant regulome
A comprehensive data portal to explore plant regulomes is still unavailable. Here, the authors develop a web-based platform ChIP-Hub in the ENCODE standards and demonstrate its applications in the identification of hierarchical regulatory network, tissue-specific chromatin dynamics, putative enhancers and chromatin states.
- Liang-Yu Fu
- , Tao Zhu
- & Dijun Chen
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Article
| Open AccessOrgo-Seq integrates single-cell and bulk transcriptomic data to identify cell type specific-driver genes associated with autism spectrum disorder
Cerebral organoids can be used to gain insights into neuropsychiatric disorders. Here the authors carry out RNAseq characterization from organoids derived from donors with autism spectrum disorder to identify associated cell type specific driver genes.
- Elaine T. Lim
- , Yingleong Chan
- & George M. Church
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Article
| Open AccessDynamic nucleosome landscape elicits a noncanonical GATA2 pioneer model
Here the authors provide a multi-omic study of the nucleosome landscape in LNCaP cells and observe nine functional nucleosome states each with characteristic nucleosome footprints. Upon androgen stimulation, they observed changes in these nucleosome states accompanied by changes in binding and function of pioneer factors, including GATA2.
- Tianbao Li
- , Qi Liu
- & Victor X. Jin
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| Open AccessThe case for increasing diversity in tissue-based functional genomics datasets to understand human disease susceptibility
Tissue-based functional genomics resources including molecular quantitative trait loci datasets lack diversity in ancestry and tissue types and thus are inadequate for comprehensively investigating gene regulation. Global efforts to increase the tissue diversity will help achieve more equitable medical care.
- Erping Long
- , Montserrat García-Closas
- & Jiyeon Choi
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Article
| Open AccessDELE1 tracks perturbed protein import and processing in human mitochondria
Human mitochondria experience substantial stress and malfunction in neurological diseases. Here, the authors reveal DELE1 as a multimodal sensor of protein import and processing defects, rationalizing mitochondrial stress integration.
- Evelyn Fessler
- , Luisa Krumwiede
- & Lucas T. Jae
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Article
| Open AccessGenetic variation of macronutrient tolerance in Drosophila melanogaster
Responses to diet composition may be linked to susceptibility to metabolic diseases such as type 2 diabetes. Here the authors report that Drosophila melanogaster displays genetic variation in survival on different diets and describe the importance for JNK-pathway and a conserved orphan nuclear hormone receptor tailless in regulating sugar tolerance.
- E. Havula
- , S. Ghazanfar
- & A. M. Senior
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Article
| Open AccessMassively parallel reporter perturbation assays uncover temporal regulatory architecture during neural differentiation
How gene regulatory elements regulate gene expression during cellular differentiation remains largely unknown. Here the authors use perturbation-based massively parallel reporter assays at early time points of neural differentiation to systematically characterize how regulatory elements and motifs within them guide different transcriptional patterns.
- Anat Kreimer
- , Tal Ashuach
- & Nadav Ahituv
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Article
| Open AccessTransposon insertional mutagenesis of diverse yeast strains suggests coordinated gene essentiality polymorphisms
Epistasis can lead to different phenotypic consequences from the same mutation. Here the authors carry out a genome-wide analysis of conditionally essential genes in yeast, finding that gene essentiality changes tend to occur concordantly among components of the same protein complex or metabolic pathway.
- Piaopiao Chen
- , Agnès H. Michel
- & Jianzhi Zhang
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Article
| Open AccessBenchmarking of SpCas9 variants enables deeper base editor screens of BRCA1 and BCL2
Numerous rationally-designed and directed-evolution variants of SpCas9 have been reported to expand the utility of CRISPR technology. Here the authors make comparisons of numerous Cas9 variants, nominate options for base editing screens with denser coverage with A>G and C>T base editing screens and identify loss-of-function mutations in BRCA1 and Venetoclax-resistant mutations in BCL2.
- Annabel K. Sangree
- , Audrey L. Griffith
- & John G. Doench
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Article
| Open AccessXenogeneic silencing strategies in bacteria are dictated by RNA polymerase promiscuity
Bacteria use specific silencing proteins to prevent spurious transcription of horizontally acquired DNA. Here, Forrest et al. describe differences in silencing strategies between E. coli and Bacillus subtilis, driven by the respective specificities of the silencing protein and the RNA polymerase in each organism.
- David Forrest
- , Emily A. Warman
- & David C. Grainger
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Article
| Open AccessGenome-wide functional screens enable the prediction of high activity CRISPR-Cas9 and -Cas12a guides in Yarrowia lipolytica
The successful use of CRISPR-based mutagenesis in non-conventional microorganisms requires high activity sgRNAs. Here, the authors present DeepGuide, a neural network-based architecture, that learns from genome-wide CRISPR activity profiles to accurately design Cas9 and Cas12a sgRNAs with high activity in the oleaginous yeast Yarrowia lipolytica.
- Dipankar Baisya
- , Adithya Ramesh
- & Ian Wheeldon
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Article
| Open AccessA pan-CRISPR analysis of mammalian cell specificity identifies ultra-compact sgRNA subsets for genome-scale experiments
Context specificity confounds genetic analysis and prevents reproducible genome engineering. Here, the authors report a pan-CRISPR analysis of specificity in mammalian cells and identify ultra-compact sgRNA subsets for genome-scale screens.
- Boyang Zhao
- , Yiyun Rao
- & Justin R. Pritchard
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Article
| Open AccessParallel functional assessment of m6A sites in human endodermal differentiation with base editor screens
N6-methyladenosine (m6A) plays important role in lineage specifications of embryonic stem cells, but its role at specific sites has not been assessed. Here the authors develop an adenine editor-based strategy, and systematically identify functional m6A sites that control lineage decisions in human embryonic stem cells.
- Weisheng Cheng
- , Fang Liu
- & Jinkai Wang
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Article
| Open AccessThe genetic architecture underlying prey-dependent performance in a microbial predator
What prevents a generalist predator from evolving and outperforming specialist predators? By combing analyses of natural variation with experimental evolution, Stewart et al. suggest that predator variation persists because most mutations have prey-specific effects, which results in relaxed selection
- Balint Stewart
- , Nicole Gruenheit
- & Christopher R. L. Thompson
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Article
| Open AccessBioinformatic and cell-based tools for pooled CRISPR knockout screening in mosquitos
Forward genetic approaches such as CRISPR screens are powerful ways to identify essential genes and those that influence host-pathogen interactions. Here the authors design a bioinformatics portal for sgRNA design and a recombination-mediated cassette system for delivery into mosquito cell lines.
- Raghuvir Viswanatha
- , Enzo Mameli
- & Norbert Perrimon
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Article
| Open AccessSingle cell multi-omic analysis identifies a Tbx1-dependent multilineage primed population in murine cardiopharyngeal mesoderm
Perturbations of the cardiopharyngeal mesoderm can lead to congenital defects in individuals with 22q11.2 deletion syndrome. Here the authors use single cell RNA-sequencing to identify a multilineage primed population within the mesoderm, marked by Tbx1, which has bipotent properties to form cardiac and branchiomeric muscle cells.
- Hiroko Nomaru
- , Yang Liu
- & Bernice E. Morrow
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Article
| Open AccessLeveraging machine learning essentiality predictions and chemogenomic interactions to identify antifungal targets
The analysis of essential genes in pathogens can be used to discover potential antimicrobial targets. Here, the authors use a machine learning model and chemogenomic analyses to generate genome-wide gene essentiality predictions for the fungal pathogen Candida albicans, define the function of three uncharacterized essential genes, and identify the target of a new antifungal compound.
- Ci Fu
- , Xiang Zhang
- & Leah E. Cowen
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Article
| Open AccessCSC software corrects off-target mediated gRNA depletion in CRISPR-Cas9 essentiality screens
Off-target effects often confound the interpretation of CRISPR screens. Here, the authors introduce a computational method that corrects for off-targets in gRNA depletion assays, circumventing the need to completely discard unspecific guides.
- Alexendar R. Perez
- , Laura Sala
- & Joana A. Vidigal
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Article
| Open AccessMassively parallel interrogation of protein fragment secretability using SECRiFY reveals features influencing secretory system transit
The exact protein features that control passage through the eukaryotic secretory system remain largely unknown. Here the authors report SECRiFY which they use to evaluate the secretory potential of polypeptides on a proteome-wide scale in yeast, revealing a role for flexibility and intrinsic disorder.
- Morgane Boone
- , Pathmanaban Ramasamy
- & Nico Callewaert
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Article
| Open AccessAn innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions
Human polymorphisms in nicotinic acetylcholine receptor genes have been linked to both smoking and lung diseases like Chronic Obstructive Pulmonary Disease (COPD) or lung cancer. Here the authors identify a direct role for a human coding polymorphism in COPD-like lesions independent of smoke or nicotine exposure.
- Julie Routhier
- , Stéphanie Pons
- & Uwe Maskos
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Article
| Open AccessBAMboozle removes genetic variation from human sequence data for open data sharing
Transparent data sharing is central to scientific progress, but limited for human sequencing data because of patient privacy concerns. Here, the authors propose an approach that removes certain types of genetic information in sequencing data, without affecting count-based downstream analyses.
- Christoph Ziegenhain
- & Rickard Sandberg
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Article
| Open AccessEngineering digitizer circuits for chemical and genetic screens in human cells
Cell-based transcriptional reporters are an invaluable part of highthroughput screening, but many such reporters have weak or transient responses. Here, the authors describe a digitizer circuit for amplifying reporter activity, increasing sensitivity, and retaining memory of pathway activation.
- Nicole M. Wong
- , Elizabeth Frias
- & Wilson W. Wong
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Article
| Open AccessEnhancer-associated H3K4 methylation safeguards in vitro germline competence
While inductive signals controlling germline specification are well characterized, the intrinsic factors that allow epiblast cells to respond to such signals remain largely unknown. Here the authors use in vitro differentiated primordial germ cells to show that partial retention of histone H3K4 monomethylation within relevant enhancers is important for germline competence and specification.
- Tore Bleckwehl
- , Giuliano Crispatzu
- & Álvaro Rada-Iglesias
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Article
| Open AccessConfronting false discoveries in single-cell differential expression
Differential expression analysis of single-cell transcriptomics allows scientists to dissect cell-type-specific responses to biological perturbations. Here, the authors show that many commonly used methods are biased and can produce false discoveries.
- Jordan W. Squair
- , Matthieu Gautier
- & Grégoire Courtine
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Article
| Open AccessNeofunctionalization of an ancient domain allows parasites to avoid intraspecific competition by manipulating host behaviour
Evolutionary arms races can drive adaptations in hosts and parasites as well as among competing parasites. A combination of multi-omics and functional tests identifies a set of genes that allow a parasitic wasp to minimize intraspecific competition by inducing hosts to escape before more wasps can parasitize them.
- Jiani Chen
- , Gangqi Fang
- & Jianhua Huang
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Article
| Open AccessA functional genomics pipeline identifies pleiotropy and cross-tissue effects within obesity-associated GWAS loci
Many genetic loci have been linked to obesity, but knowledge of their functional mechanisms is limited. Here, the authors perform reporter assays and temporal functional genomics data generation to characterize obesity genetic loci and find that loci often harbor multiple functional variants.
- Amelia C. Joslin
- , Débora R. Sobreira
- & Marcelo A. Nóbrega
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Article
| Open AccessFunctional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation
Identifying causal variants at GWAS loci is important to understand disease mechanisms. Here the authors use massively parallel reporter assays to identify type 2 diabetes-associated variants that alter cis-regulatory activity, narrowing in on the causal variants and genetic mechanisms behind the disease.
- Shubham Khetan
- , Susan Kales
- & Michael L. Stitzel
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Article
| Open AccessAging, inflammation and DNA damage in the somatic testicular niche with idiopathic germ cell aplasia
Molecular mechanisms associated with human germ cell aplasia in infertile men remain undefined. Here the authors perform single-cell transcriptome profiling to highlight differentially expressed genes and pathways in each somatic cell type in testes of men with idiopathic germ cell aplasia.
- Massimo Alfano
- , Anna Sofia Tascini
- & Andrea Salonia
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Article
| Open AccessA nutrient-responsive hormonal circuit mediates an inter-tissue program regulating metabolic homeostasis in adult Drosophila
Maintaining metabolic homeostasis during feeding and fasting states is critical to animal survival. Here the authors show that Capa hormone signaling, homologs to mammalian Neuromedin U, helps control homeostasis via regulation of nutrient uptake and energy storage in Drosophila.
- Takashi Koyama
- , Selim Terhzaz
- & Kenneth V. Halberg
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Article
| Open AccessA single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis
Identifying causal variants and genes is an essential step in interpreting GWAS loci. Here, the authors investigate a kidney disease GWAS locus with functional genomics data, CRISPR editing and mouse experiments to identify DPEP1 and CHMP1A as putative kidney disease genes via ferroptosis.
- Yuting Guan
- , Xiujie Liang
- & Katalin Susztak
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Article
| Open AccessMulti-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases
Alcohol use disorder and drinks per week both have been studied genetically and have different correlations with psychiatric diseases. Here the authors integrate multi-omics data to identify unique and shared variants, genes and pathways for alcohol use disorder and drinks per week.
- Manav Kapoor
- , Michael J. Chao
- & Alison Goate
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Article
| Open AccessThe molecular basis, genetic control and pleiotropic effects of local gene co-expression
Local gene co-expression is found throughout the genome, but systematic analysis of these co-expressed genes is needed. Here, the authors identify local co-expressed genes in 49 tissues and characterize the genetic variants which may affect their expression and contribute to disease.
- Diogo M. Ribeiro
- , Simone Rubinacci
- & Olivier Delaneau
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Article
| Open AccessMultiplexed functional genomic analysis of 5’ untranslated region mutations across the spectrum of prostate cancer
Mutations in 5’ untranslated regions (UTRs) have a functional role in gene expression in cancer. Here, the authors develop a sequencing-based high throughput functional assay named PLUMAGE and show the effects of these mutations on gene expression and their association with clinical outcomes in prostate cancer.
- Yiting Lim
- , Sonali Arora
- & Andrew C. Hsieh
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Article
| Open AccessThe extracellular contractile injection system is enriched in environmental microbes and associates with numerous toxins
The extracellular Contractile Injection System (eCIS) is a toxin-delivery particle that mediates interactions between bacteria and their invertebrate hosts. Here, the authors catalogue eCIS loci from 1,249 prokaryotic genomes, showing enrichment in non-pathogenic environmental microbes, and identifying eCIS-associated toxins that inhibit the growth of bacteria and/or yeast.
- Alexander Martin Geller
- , Inbal Pollin
- & Asaf Levy
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Article
| Open AccessTissue context determines the penetrance of regulatory DNA variation
The functional consequences of variation in human regulatory DNA depend on the local chromatin environment and the cell/tissue context. Here the authors use highly diverged hybrid mice to study genetic effects on DNA accessibility in vivo across multiple cell and tissue types.
- Jessica M. Halow
- , Rachel Byron
- & Matthew T. Maurano
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Article
| Open AccessHotspot exons are common targets of splicing perturbations
Splicing-disrupting mutations are linked to diseases. By employing a machine learning approach, the authors show that certain exons, termed hotspot exons, are enriched for splicing-disruption variants and susceptible to splicing perturbations.
- David T. Glidden
- , Jeramiah L. Buerer
- & William G. Fairbrother
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Article
| Open AccessA compendium and comparative epigenomics analysis of cis-regulatory elements in the pig genome
To date, little is known about the regulatory landscape of the pig genome. Here, the authors characterize cis-regulatory elements in the pig genome using RNA-seq, ChIP-Seq and ATAC-seq, finding a higher degree of usage conservation between pig and human than mouse and human.
- Yunxia Zhao
- , Ye Hou
- & Shuhong Zhao
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Article
| Open AccessProtein kinase A controls the hexosamine pathway by tuning the feedback inhibition of GFAT-1
The glutamine fructose-6-phosphate amidotransferase 1 (GFAT-1) is the rate-limiting enzyme in the hexosamine pathway producing uridine 5’-diphospho-N-acetyl-D-glucosamine (UDP-GlcNAc), an essential glycosylation precursor. Here, the authors dissect the mechanisms of GFAT-1 regulation by protein kinase A (PKA)-mediated phosphorylation.
- Sabine Ruegenberg
- , Felix A. M. C. Mayr
- & Martin S. Denzel
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Article
| Open AccessMutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation
Aging is associated with declining protein homeostasis. Here, using a chemical mutagenesis screen for lifespan extension in C. elegans, the authors report that inhibition of the integrated stress response enhances longevity and protein homeostasis in a manner dependent on kin-35, without reducing protein synthesis.
- Maxime J. Derisbourg
- , Laura E. Wester
- & Martin S. Denzel
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Article
| Open AccessCortical structural differences in major depressive disorder correlate with cell type-specific transcriptional signatures
The correlation between brain structural changes in major depressive disorder (MDD) and gene expression is unclear. Here, the authors explore the correlation between cell type-specific gene expression changes and cortical structural difference in individuals with major depressive disorder.
- Jiao Li
- , Jakob Seidlitz
- & Wei Liao
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Article
| Open AccessIntegration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes
This study integrates Alzheimer’s disease (AD) GWAS data with myeloid cell genomics, and reports that myeloid active enhancers are most burdened by AD risk alleles. The authors also nominate candidate causal regulatory elements, variants and genes that likely modulate the risk for AD.
- Gloriia Novikova
- , Manav Kapoor
- & Alison M. Goate
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Article
| Open AccessGlobal discovery of lupus genetic risk variant allelic enhancer activity
Thousands of genetic variants have been associated with lupus, but causal variants and mechanisms are unknown. Here, the authors combine a massively parallel reporter assay with genome-wide ChIP experiments to identify risk variants with allelic enhancer activity mediated through transcription factor binding.
- Xiaoming Lu
- , Xiaoting Chen
- & Leah C. Kottyan
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Article
| Open AccessProtein context shapes the specificity of SH3 domain-mediated interactions in vivo
The SRC Homology 3 (SH3) domains mediate protein–protein interactions (PPIs). Here, the authors assess the SH3-mediated PPIs in yeast, and show that the identity of the protein itself and the position of the SH3 both affect the interaction specificity and thus the PPI-dependent cellular functions.
- Ugo Dionne
- , Émilie Bourgault
- & Christian R. Landry
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Article
| Open AccessChromatin information content landscapes inform transcription factor and DNA interactions
Interaction between transcription factors and chromatin is fundamental for genome organization and regulation. Here, the authors use information theory to measure signatures of organized chromatin resulting from transcription factor-chromatin interactions, termed chromatin information enrichment, and find that variations in the information encoded in chromatin architecture reflects functional biological variation.
- Ricardo D’Oliveira Albanus
- , Yasuhiro Kyono
- & Stephen C. J. Parker
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Article
| Open AccessA molecular quantitative trait locus map for osteoarthritis
Understanding the molecular effects of disease variants in relevant tissues is essential to understanding and treating disease. Here, the authors discover expression and protein quantitative trait loci in cartilage and synovium from 115 osteoarthritis patients to pinpoint genes of action and potential drug treatments.
- Julia Steinberg
- , Lorraine Southam
- & Eleftheria Zeggini
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Article
| Open AccessDeterminants of genome-wide distribution and evolution of uORFs in eukaryotes
Upstream open reading frames (uORFs) have widespread regulatory functions in eukaryotes, their genomic distribution and evolution is understudied. Here, the authors characterise ~17 million putative uORFs across 478 eukaryotic species, showing how evolution has shaped uORF contents and distribution.
- Hong Zhang
- , Yirong Wang
- & Jian Lu
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Article
| Open AccessLETR1 is a lymphatic endothelial-specific lncRNA governing cell proliferation and migration through KLF4 and SEMA3C
Long noncoding RNAs regulate tissue-specific gene expression. Here the authors profile lineage-specific lncRNAs in human dermal lymphatic and blood vascular endothelial cells (LECs and BECs) and show a role of LEC-specific lncRNA, LETR1, in cell proliferation and migration.
- Luca Ducoli
- , Saumya Agrawal
- & Michael Detmar