Featured
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| Open AccessUncovering transcriptional dark matter via gene annotation independent single-cell RNA sequencing analysis
Conventional single-cell RNA sequencing analysis rely on genome annotations that may be incomplete or inaccurate especially for understudied organisms. Here the authors present a bioinformatic tool that leverages single-cell data to uncover biologically relevant transcripts beyond the best available genome annotation.
- Michael F. Z. Wang
- , Madhav Mantri
- & Iwijn De Vlaminck
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Article
| Open AccessVariable number tandem repeats mediate the expression of proximal genes
Variable number tandem repeats (VNTRs) are implicated in human diseases yet have been difficult to analyse computationally. Here, the authors describe a neural network method, adVNTR-NN, that allows rapid and accurate genotyping of VNTRs from large whole genome sequencing datasets.
- Mehrdad Bakhtiari
- , Jonghun Park
- & Vineet Bafna
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Article
| Open AccessFTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell
The demethylase FTO was shown to remove on N6-methyladenosine (m6A) and N6, 2’-O-dimethyladenosine (m6Am) modifications on RNAs. Here the authors show that FTO impedes cancer stem cell-like abilities in colorectal cancer cells through its m6Am demethylase activity, not through internal m6A demethylase activity.
- Sébastien Relier
- , Julie Ripoll
- & Alexandre David
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Article
| Open AccessInterplay of BAF and MLL4 promotes cell type-specific enhancer activation
The SWI/SNF complex BAF and the histone H3K4 methyltransferase MLL4 (KMT2D) play critical roles in enhancer activation, however the interplay between them has remained unclear. Here the authors show that BAF and MLL4 are interdependent in promoting enhancer activation by lineage-determining transcription factors during adipogenesis.
- Young-Kwon Park
- , Ji-Eun Lee
- & Kai Ge
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Article
| Open AccessA scalable unified framework of total and allele-specific counts for cis-QTL, fine-mapping, and prediction
Methods for eQTL mapping from total and allele-specific gene expression typically are too computationally heavy to apply to large scale studies. Here, the authors describe a computationally efficient method to identify eQTLs, fine-map and predict expression from total and allele-specific gene expression
- Yanyu Liang
- , François Aguet
- & Hae Kyung Im
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Article
| Open AccessStructure of mammalian Mediator complex reveals Tail module architecture and interaction with a conserved core
The Mediator complex regulates RNA polymerase II transcription in all eukaryotes. The mammalian Mediator cryo-EM structure reveals the architecture of previously unresolved Tail module and suggests its regulatory role in the complex conformation and interactions.
- Haiyan Zhao
- , Natalie Young
- & Francisco J. Asturias
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Article
| Open AccessThe secreted endoribonuclease ENDU-2 from the soma protects germline immortality in C. elegans
The question as to how the soma regulates the germline has been much studied. Here, the authors show in C. elegans that the poly-U specific endoribonuclease ENDU-2 is secreted from the soma and taken-up by the germline, binding mature mRNA, repressing expression of somatic transcripts and maintaining germline immortality.
- Wenjing Qi
- , Erika D. V. Gromoff
- & Ralf Baumeister
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Article
| Open AccessThe acquisition of molecular drivers in pediatric therapy-related myeloid neoplasms
Paediatric therapy-related myeloid neoplasms (tMN) have a dismal prognosis and have not been comprehensively profiled. Here the authors characterise the molecular landscape of 84 paediatric tMN patients, and find that, unlike adult tMNs, these do not emerge from pre-existing clones and that MECOM dysregulation is frequent.
- Jason R. Schwartz
- , Jing Ma
- & Jeffery M. Klco
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Article
| Open AccessMultifunctional evolution of B and AGL6 MADS box genes in orchids
B class AP3/PI and AGL6-like MADS proteins determine lips and sepals/petals identities in orchids. Here, the authors characterize the extended function of OAP3/OPI/OAGL6 in regulating the specific structure of the lateral sepals, pigmentation/senescence of the perianth and abscission of the pedicel.
- Hsing-Fun Hsu
- , Wei-Han Chen
- & Chang-Hsien Yang
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Article
| Open AccessSLE non-coding genetic risk variant determines the epigenetic dysfunction of an immune cell specific enhancer that controls disease-critical microRNA expression
Enhancers shape gene expression patterns and are involved in disease pathogenesis. Here the authors demonstrate a strategy to screen functional regulatory elements for non-coding RNAs ― illustrated with miR-146a ― and link autoimmune disease risk genetic variants to autoimmune disease etiology.
- Guojun Hou
- , Isaac T. W. Harley
- & Nan Shen
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Article
| Open AccessRapid parallel adaptation despite gene flow in silent crickets
Gene flow is classically thought to impede local adaptation via parallel evolution. However, a genomic study on Hawaiian crickets from different island populations finds evidence of parallel adaptation to the same lethal parasitoid in spite of strong ongoing gene flow.
- Xiao Zhang
- , Jack G. Rayner
- & Nathan W. Bailey
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Article
| Open AccessSingle-cell atlas of the first intra-mammalian developmental stage of the human parasite Schistosoma mansoni
Schistosomes undergo several develepmental stages during infection of humans. Here, the authors perform single-cell RNA sequencing on the earliest intra-mammalian stage of Schistosoma mansoni and generate a comprehensive cell-type atlas for this human parasite.
- Carmen Lidia Diaz Soria
- , Jayhun Lee
- & Matthew Berriman
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Article
| Open AccessSingle-nucleus RNA-seq identifies transcriptional heterogeneity in multinucleated skeletal myofibers
Mammalian skeletal muscle is composed of multinucleated myofibers, containing hundreds of nuclei that coordinate cellular function. Here, the authors show that single-nucleus RNA-sequencing reveals rare and emergent myonuclear populations, and uncovers dynamic transcriptional heterogeneity in development and aging.
- Michael J. Petrany
- , Casey O. Swoboda
- & Douglas P. Millay
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Article
| Open AccessSingle-nucleus transcriptomics reveals functional compartmentalization in syncytial skeletal muscle cells
The transcriptional programs of nuclei in the muscle syncytium were assumed to be homogenous except at the neuromuscular and myotendinous junctions. Here, using single-nucleus transcriptomics, the authors reveal a previously unrecognized diversity and dynamics of myonuclear transcriptional programs.
- Minchul Kim
- , Vedran Franke
- & Carmen Birchmeier
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Article
| Open AccessEngineering rules that minimize germline silencing of transgenes in simple extrachromosomal arrays in C. elegans
C. elegans has strong repressive mechanisms that silence transgenes in the germline. Here the authors elucidate the design rules for efficient germline expression.
- Mohammed D. Aljohani
- , Sonia El Mouridi
- & Christian Frøkjær-Jensen
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Article
| Open AccessMuscle progenitor specification and myogenic differentiation are associated with changes in chromatin topology
Chromatin structure and topology play important roles in the regulation of gene expression. Here the authors study the spatio-temporal re-organization of promoter-enhancer interactions in pluripotent ES and skeletal muscle stem cells and the corresponding impact on gene expression as a consequence of myogenic commitment and differentiation.
- Nan Zhang
- , Julen Mendieta-Esteban
- & Brian David Dynlacht
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Article
| Open AccessPogz deficiency leads to transcription dysregulation and impaired cerebellar activity underlying autism-like behavior in mice
POGZ is an autism spectrum disorder risk gene. How POGZ mutations result in ASD is unclear and animal models are lacking. Here, the authors generate a brain specific Pogz deficient mouse presenting ASD-like behaviour and show the effects of Pogz deficiency in the cerebellum.
- Reut Suliman-Lavie
- , Ben Title
- & Sagiv Shifman
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Article
| Open AccessMolecular estimation of neurodegeneration pseudotime in older brains
The limited understanding of the temporal molecular changes in late-onset Alzheimer’s disease hinder the development of therapeutic treatment. The authors use manifold learning to develop a molecular model for disease progression from RNASeq data from human postmortem brain samples.
- Sumit Mukherjee
- , Laura Heath
- & Benjamin A. Logsdon
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| Open AccessGenotype by environment interaction for gene expression in Drosophila melanogaster
Huang et al. show that developing under different temperatures changes the genetic architecture of regulatory variation in Drosophila melanogaster gene expression yet the co-expression network remains robust. Data suggest that stabilizing selection on gene expression may promote co-expression network robustness.
- Wen Huang
- , Mary Anna Carbone
- & Trudy F. C. Mackay
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Article
| Open AccessSingle-cell RNA cap and tail sequencing (scRCAT-seq) reveals subtype-specific isoforms differing in transcript demarcation
Most single-cell RNA sequencing methods have limited ability to profile the transcriptome at isoform resolution. Here the authors develop scRCAT-seq to characterize the 5′- and 3′-ends of transcripts in single cells, and identify cell-type specific alternative transcript isoforms.
- Youjin Hu
- , Jiawei Zhong
- & Yizhi Liu
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Article
| Open AccessReconstructing the maize leaf regulatory network using ChIP-seq data of 104 transcription factors
Transcriptional factors (TFs) bind in a combinatorial fashion to specify the on-and-off states of genes in a complex and redundant regulatory network. Here, the authors construct the transcription regulatory network in maize leaf using 104 TFs ChIP-seq data and train machine learning models to predict TF binding and colocalization.
- Xiaoyu Tu
- , María Katherine Mejía-Guerra
- & Silin Zhong
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Article
| Open AccessIntegrative genomic analysis reveals mechanisms of immune evasion in P. falciparum malaria
Here, the authors identify signatures of miRNA expression differentiation associated with Plasmodium falciparum infection and parasitemia in a longitudinal pediatric cohort in Burkina Faso. In particular, expression of several miRNAs known to promote lymphocyte cell death is affected during infection.
- Mame Massar Dieng
- , Aïssatou Diawara
- & Youssef Idaghdour
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Article
| Open AccessGenome-wide chromatin accessibility is restricted by ANP32E
Chromatin state underlies cellular function, and transcription factor binding patterns along with epigenetic marks define chromatin state. Here the authors show that the histone chaperone ANP32E functions through regulation of H2A.Z to restrict genome-wide chromatin accessibility and to inhibit gene transcriptional activation.
- Kristin E. Murphy
- , Fanju W. Meng
- & Patrick J. Murphy
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Article
| Open AccessPQM-1 controls hypoxic survival via regulation of lipid metabolism
Animals respond to hypoxic stress by adjusting metabolic processes to balance survival and reproduction. Here the authors identify the transcription factor PQM-1 as a metabolic regulator that balances hypoxic lipid and carbohydrate metabolism in C. elegans to limit somatic integrity and promote progeny survival.
- Thomas Heimbucher
- , Julian Hog
- & Coleen T. Murphy
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Article
| Open AccessMendelian randomization while jointly modeling cis genetics identifies causal relationships between gene expression and lipids
Mendelian randomization is a useful tool to infer causal relationships between traits, but can be confounded by the presence of pleiotropy. Here, the authors have developed MR-link, a Mendelian randomization method which accounts for unobserved pleiotropy and linkage disequilibrium between instrumental variables.
- Adriaan van der Graaf
- , Annique Claringbould
- & Serena Sanna
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Article
| Open AccessIntegrative genomics identifies a convergent molecular subtype that links epigenomic with transcriptomic differences in autism
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with repetitive and restrictive behaviours. Here the authors integrate mRNA expression, miRNA expression, DNA methylation, and histone acetylation datasets from a collection of post mortem brain tissues and identify a convergent molecular subtype of ASD.
- Gokul Ramaswami
- , Hyejung Won
- & Daniel H. Geschwind
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Article
| Open AccessPolyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction
Metabolic reprogramming during Dietary Restriction (DR) activates cytoprotective gene expression. Here the authors show that PUFAs generated during DR signal via the p38-MAPK pathway to enhance cytoprotective gene expression, contributing to increased longevity.
- Manish Chamoli
- , Anita Goyala
- & Arnab Mukhopadhyay
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Article
| Open AccessAmalgamated cross-species transcriptomes reveal organ-specific propensity in gene expression evolution
Multicellularity requires complex coordinated gene expression. Fukushima and Pollock find that gene expression in different organs is likely to constrain future patterns of gene expression evolution, particularly following gene duplication.
- Kenji Fukushima
- & David D. Pollock
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Article
| Open AccessGenetically controlled membrane synthesis in liposomes
Controlled membrane synthesis in liposomes is a prerequisite for synthetic systems emulating the fundamental properties of living cells. Here authors present that a de novo synthesized metabolic pathway converts precursors into a variety of lipids, including the constituents of the parental liposome.
- Duco Blanken
- , David Foschepoth
- & Christophe Danelon
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Article
| Open AccessCORE GREML for estimating covariance between random effects in linear mixed models for complex trait analyses
Linear mixed models have bias due to the assumed independence between random effects. Here, the authors describe a genome-based restricted maximum likelihood, CORE GREML, which estimates covariance between random effects. Application to UK Biobank data highlights this as an important parameter for multi-omics analyses of phenotypic variance.
- Xuan Zhou
- , Hae Kyung Im
- & S. Hong Lee
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Article
| Open AccessA single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders
The substantia nigra is important in neurological disease, particularly movement disorders. Here the authors provide a single cell transcriptomic atlas for the human substantia nigra.
- Devika Agarwal
- , Cynthia Sandor
- & Caleb Webber
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Article
| Open AccessInteraction of the pioneer transcription factor GATA3 with nucleosomes
GATA 3 functions as a pioneer factor during cellular reprogramming. Here the authors delineate nucleosome positioning relative to GATA3 binding motifs and describe the structure of a GATA3–nucleosome complex; providing insight into how a pioneer factor interacts with nucleosomes and catalyze their local remodelling to produce an accessible enhancer.
- Hiroki Tanaka
- , Yoshimasa Takizawa
- & Hitoshi Kurumizaka
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Article
| Open AccessDisease-associated KIF3A variants alter gene methylation and expression impacting skin barrier and atopic dermatitis risk
Genetic variants in KIF3A are associated with atopic dermatitis (AD). Here, the authors identify two AD-risk alleles that show high methylation resulting in lower KIF3A expression. Mice with epidermis-specific loss of Kif3a show disrupted skin barrier homeostasis and increased AD susceptibility.
- Mariana L. Stevens
- , Zhonghua Zhang
- & Gurjit K. Khurana Hershey
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Article
| Open AccessGWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer
Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. Here, the authors conduct a GWAS and suggest protective effect of higher TSH on risk of thyroid cancer and goitre.
- Wei Zhou
- , Ben Brumpton
- & Bjørn Olav Åsvold
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Article
| Open AccessTesting and controlling for horizontal pleiotropy with probabilistic Mendelian randomization in transcriptome-wide association studies
Transcriptome-wide association studies integrate GWAS and transcriptome data to examine the molecular mechanisms underlying disease etiology. Here the authors present PMR-Egger, a powerful TWAS method based on probabilistic Mendelian Randomization.
- Zhongshang Yuan
- , Huanhuan Zhu
- & Xiang Zhou
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Article
| Open AccessNeonatal genetics of gene expression reveal potential origins of autoimmune and allergic disease risk
Some immune-mediated diseases may originate in early childhood. The authors mapped eQTLs and response eQTLs to various stimuli in neonatal myeloid cells and T cells, and revealed their potential role in immune-mediated diseases using colocalisation and Mendelian randomisation.
- Qin Qin Huang
- , Howard H. F. Tang
- & Michael Inouye
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Article
| Open AccessSingle-particle imaging of stress-promoters induction reveals the interplay between MAPK signaling, chromatin and transcription factors
Mitogen-Activated Protein Kinases integrate extracellular information in all eukaryotic cells. Using a live mRNA reporter, here the authors monitor transcriptional bursting in Saccharomyces cerevisiae upon hyper-osmotic shock and characterize the influence of MAPK signalling, chromatin and transcription factors on the dynamics of transcription.
- Victoria Wosika
- & Serge Pelet
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Article
| Open AccessProperties of structural variants and short tandem repeats associated with gene expression and complex traits
Genetic variation associated with gene expression changes has mostly been studied in the context of single nucleotide variants. Here, Jakubosky et al. report eQTL analysis of structural variants and short tandem repeats and find properties, such as length of variation, that affect the association.
- David Jakubosky
- , Matteo D’Antonio
- & Kelly A. Frazer
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Article
| Open AccessA multi-omics analysis reveals the unfolded protein response regulon and stress-induced resistance to folate-based antimetabolites
The unfolded protein response (UPR) is a stress response pathway implicated in numerous diseases and chemotherapy resistance. Here, the authors define the UPR regulon with a multi-omics strategy, uncovering changes to mitochondrial one-carbon metabolism and concomitant resistance to folate-based therapeutics.
- Stefan Reich
- , Chi D. L. Nguyen
- & Jan Medenbach
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Article
| Open AccessTranscriptional and imaging-genetic association of cortical interneurons, brain function, and schizophrenia risk
Interneuron subtypes have distinct properties and spatial distributions. Here, the authors show that the molecular-genetic basis of cortical resting-state brain function is shaped by distributions of interneuron-related transcripts and may capture individual differences in schizophrenia risk.
- Kevin M. Anderson
- , Meghan A. Collins
- & Avram J. Holmes
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Article
| Open AccessInterpreting molecular similarity between patients as a determinant of disease comorbidity relationships
Disease comorbidity is attracting increasing attention, but the involvement of molecular factors in forecasting risk of a disease in the presence of other diseases is poorly understood. Here the authors build a disease interaction network based on gene expression profile and discover new comorbidity relationships in patient subgroups.
- Jon Sánchez-Valle
- , Héctor Tejero
- & Alfonso Valencia
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Article
| Open AccessGenome and single-cell RNA-sequencing of the earthworm Eisenia andrei identifies cellular mechanisms underlying regeneration
The mechanisms regulating regeneration of the earthworm are unclear. Here, the authors use genomic and transcriptomic analysis of the earthworm Eisenia andrei together with Hi-C analysis to identify genes involved and show activation of LINE2 transposable elements on regeneration.
- Yong Shao
- , Xiao-Bo Wang
- & Dong-Dong Wu
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Article
| Open AccessGenomic adaptations to aquatic and aerial life in mayflies and the origin of insect wings
Genomic studies of paleopteran insects, such as mayflies, are needed to reconstruct early insect evolution. Here, Almudi and colleagues present the genome of the mayfly Cloeon dipterum and use transcriptomics to characterize its adaptations to distinct habitats and the origin of insect wings.
- Isabel Almudi
- , Joel Vizueta
- & Fernando Casares
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Article
| Open AccessTranscript isoform sequencing reveals widespread promoter-proximal transcriptional termination in Arabidopsis
Gene isoforms result from variable transcription start sites (TSSs) and polyadenylation sites (PASs) at the end of transcripts. Here, the authors perform transcript isoform sequencing and find widespread promoter- proximal transcriptional termination in Arabidopsis, suggesting this may represent a checkpoint that regulates plant gene expression.
- Quentin Angelo Thomas
- , Ryan Ard
- & Sebastian Marquardt
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Article
| Open AccessDeterminants of transcription factor regulatory range
Characterization of the distance over which TF binding influences gene expression is important for inferring target genes. Here the authors study this relationship using thousands of genomic data sets, finding two classes of TFs with distinct ranges of regulatory influence modulated by chromatin states of topologically associated domains.
- Chen-Hao Chen
- , Rongbin Zheng
- & X. Shirley Liu
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Article
| Open AccessTunable genetic devices through simultaneous control of transcription and translation
Synthetic genetic circuits are sensitive to their environment and host cell, requiring many rounds of physical reassembly to achieve a desired function. Here the authors use a multi-level regulatory motif to dynamically tune the function of genetic parts as a step towards robust adaptive circuits.
- Vittorio Bartoli
- , Grace A. Meaker
- & Thomas E. Gorochowski
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Article
| Open AccessAccurate estimation of cell composition in bulk expression through robust integration of single-cell information
Traditional methods for determining cell type composition lack scalability, while single-cell technologies remain costly and noisy compared to bulk RNA-seq. Here, the authors present a highly efficient tool to measure cellular heterogeneity in bulk expression through robust integration of single-cell information.
- Brandon Jew
- , Marcus Alvarez
- & Eran Halperin
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Article
| Open AccessCysteine synthases CYSL-1 and CYSL-2 mediate C. elegans heritable adaptation to P. vranovensis infection
Caenorhabditis elegans exhibits multigenerational adaptation to bacterial infection but the mechanisms remain unclear. Here, the authors show that C. elegans parental exposure to Pseudomonas vranovensis promotes offspring resistance to infection, a process mediated by the cysteine synthases CYSL-1 and CYSL-2.
- Nicholas O. Burton
- , Cristian Riccio
- & Eric A. Miska
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Article
| Open AccessIntegrative differential expression and gene set enrichment analysis using summary statistics for scRNA-seq studies
Differential expression (DE) and gene set enrichment (GSE) analysis tend to be carried out separately. Here, the authors present iDEA (integrative Differential expression and gene set Enrichment Analysis) for the analysis of scRNAseq data which uses a Baysian approach to jointly model DE and GSE for improved power in both tasks.
- Ying Ma
- , Shiquan Sun
- & Xiang Zhou