Featured
-
-
Article
| Open Access
Maintenance of neurotransmitter identity by Hox proteins through a homeostatic mechanism
To remain functional throughout life, neuronal cells must maintain the ability to synthesize and release specific neurotransmitters. Here, the authors show that this ability critically depends on the activity of Hox proteins.
- Weidong Feng
- , Honorine Destain
- & Paschalis Kratsios
-
Article
| Open Access
A single transcription factor facilitates an insect host combating Bacillus thuringiensis infection while maintaining fitness
Plutella xylostella endures Bt toxins with no performance costs. This study reveals how, depending on the presence of the toxin, this insect modifies MAPK phosphorylation to modulate the transcription factor FTZ-F1 binding, to up- or down- regulate Bt receptors or non-receptor (resistant) paralogs.
- Zhaojiang Guo
- , Le Guo
- & Youjun Zhang
-
Article
| Open Access
Allele-specific differential regulation of monoallelically expressed autosomal genes in the cardiac lineage
The authors use allele-specific single cell transcriptomic analysis to elucidate the establishment of monoallelic gene expression in the cardiac lineage. The findings emphasize the importance of allele-specific insight into gene regulation in development, homeostasis and disease.
- Gayan I. Balasooriya
- & David L. Spector
-
Article
| Open Access
Variation in the fruit development gene POINTED TIP regulates protuberance of tomato fruit tip
While auxin has been implicated in the development of tomato fruit with pointed tips, the mechanism are largely unknown. Here, the authors report variation of a C2H2-type zinc finger transcription factor affects transcription of FUL2, which consequently regulates auxin transport and distribution to determine tomato fruit shape.
- Jianwen Song
- , Lele Shang
- & Junhong Zhang
-
Article
| Open Access
High-resolution genome topology of human retina uncovers super enhancer-promoter interactions at tissue-specific and multifactorial disease loci
The genome-wide high-resolution chromatin contact of the human retina identifies genetic control of cell-type specific gene expression pattern, missing heritability in retinopathies, and candidate genes/variants for diseases including AMD and glaucoma.
- Claire Marchal
- , Nivedita Singh
- & Anand Swaroop
-
Article
| Open Access
Decoding the spatial chromatin organization and dynamic epigenetic landscapes of macrophage cells during differentiation and immune activation
Here the authors delineate the dynamic changes in 3D genome and epigenome of differentiating macrophages and during infection with Mycobacterium tuberculosis. They reveal a role for NF-κB upon infection and identify SNPs in disease-susceptible loci, including rs1873613 that is located in the anchor of a dynamic chromatin loop.
- Da Lin
- , Weize Xu
- & Gang Cao
-
Article
| Open Access
Multi-context genetic modeling of transcriptional regulation resolves novel disease loci
Transcriptome-wide association studies (TWAS) often ignore the specificity and sharing of effects across contexts (e.g., tissues). Here, the authors describe a method to split genetic effects into context-shared and context-specific terms. They apply their method to tissue and single-cell RNA-seq and show improved power in TWAS.
- Mike Thompson
- , Mary Grace Gordon
- & Noah Zaitlen
-
Article
| Open Access
A stem cell roadmap of ribosome heterogeneity reveals a function for RPL10A in mesoderm production
How ribosomes differ in composition and function to regulate gene expression is poorly understood. Here, the authors show that ribosome composition changes during stem cell differentiation and identify a ribosomal protein that regulates production of the mesoderm lineage.
- Naomi R. Genuth
- , Zhen Shi
- & Maria Barna
-
Article
| Open Access
Systematic analysis of low-affinity transcription factor binding site clusters in vitro and in vivo establishes their functional relevance
Here the authors quantitatively characterize binding to transcription factor (TF) binding site clusters in vitro, followed by characterizing clusters in synthetic and native gene regulatory systems in yeast. They show low-affinity clusters achieve high TF occupancies in vitro and gene activation in vivo, suggesting occupancy rather than individual TF dwell times drive transcriptional activation.
- Amir Shahein
- , Maria López-Malo
- & Sebastian J. Maerkl
-
Article
| Open Access
Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1
LSD1 inhibition blocks the neuroendocrine phenotype of some small cell lung cancers (SCLCs). Here, a genome-wide CRISPR/Cas9 LSD1 inhibitor resistance screen identifies the mRNA-binding protein ZFP36L1 as a gene repressed by LSD1 that when restored inhibits SCLC neuroendocrine differentiation.
- Hsiao-Yun Chen
- , Yavuz T. Durmaz
- & Matthew G. Oser
-
Article
| Open Access
Splicing QTL analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci
Splicing QTL (sQTL), genetic variants regulating alternative splicing, can be biologically important, but complex to detect and interpret. Here, the authors identify sQTL by focusing on protein coding sequences, as an alternative to junction-based approaches.
- Kensuke Yamaguchi
- , Kazuyoshi Ishigaki
- & Yuta Kochi
-
Article
| Open Access
KLF4 recruits SWI/SNF to increase chromatin accessibility and reprogram the endothelial enhancer landscape under laminar shear stress
Here the authors studied pulmonary arterial endothelial cells (PAEC) under laminar shear stress and show that this physiologic condition markedly changes chromatin accessibility at regulatory regions, when compared to cells grown in a static state. They find that KLF4 organizes chromatin by interacting with the SWI/SNF nucleosome remodeling complex to regulate vasculo-protective gene expression.
- Jan-Renier Moonen
- , James Chappell
- & Marlene Rabinovitch
-
Article
| Open Access
Ferritin-mediated iron detoxification promotes hypothermia survival in Caenorhabditis elegans and murine neurons
Strategies to improve cold resistance are of potential biomedical interest. Here the authors demonstrate that ferritin-mediated detoxification of iron, preventing the generation of reactive oxygen species, promotes cold survival in both Caenorhabditis elegans and cultured mammalian neurons.
- Tina Pekec
- , Jarosław Lewandowski
- & Rafal Ciosk
-
Article
| Open Access
PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression
ADPKD, a common aetiology of kidney failure, is caused by heterozygous PKD1 or PKD2 mutations. Here the authors show that preventing 3′-UTR cis-inhibition of mRNAs produced by the non-inactivated PKD1/2 alleles ameliorates preclinical ADPKD.
- Ronak Lakhia
- , Harini Ramalingam
- & Vishal Patel
-
Article
| Open Access
TRIM28-dependent SUMOylation protects the adult ovary from activation of the testicular pathway
Gonadal fate in mammals is determined during embryogenesis and is actively maintained in adulthood. This study shows that E3-SUMO ligase activity of TRIM28 is required for ovarian identity maintenance and testicular-specific gene repression in mouse adult ovary; in its absence, ovarian granulosa cells transdifferentiate to Sertoli cells.
- Moïra Rossitto
- , Stephanie Déjardin
- & Francis Poulat
-
Article
| Open Access
Balanced gene dosage control rather than parental origin underpins genomic imprinting
Here the authors investigate whether for imprinted genes the parent-of-origin of the expressed allele or rather appropriate gene dosage is more important for normal development. Using the differentially methylated region of Dlk1-Dio3 gene involved in imprinting, they show that correct parent-of-origin imprinting pattern is secondary to balanced gene dosage.
- Ariella Weinberg-Shukron
- , Raz Ben-Yair
- & Yonatan Stelzer
-
Article
| Open Access
CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors
Epidermal progenitors are poised for differentiation, which allows for continual balance of self-renewal and differentiation. Here they show that the Super Elongation Complex regulates this process through direct regulation of a set of rapid response genes that involves a CDK9 activity switch.
- Sarah M. Lloyd
- , Daniel B. Leon
- & Xiaomin Bao
-
Article
| Open Access
Transcription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration in mice
Here the authors couple an integrative genomic analysis with substantial in vitro and in vivo experimental validation, identifying REST as a novel suppressor of a pro-regenerative gene program and CNS axon regeneration in mice.
- Yuyan Cheng
- , Yuqin Yin
- & Daniel H. Geschwind
-
Article
| Open Access
Postmitotic differentiation of human monocytes requires cohesin-structured chromatin
How chromatin structure and gene accessibility changes during monocyte differentiation is not clearly defined. Here the authors characterize the chromatin changes during macrophage or dendritic cell maturation from monocytes and the dependence of this upon cohesin and CTCF.
- Julia Minderjahn
- , Alexander Fischer
- & Michael Rehli
-
Article
| Open Access
A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer
Super-enhancers and their associated transcription factor networks have been shown to influence ovarian cancer biology. Here, based on an integrated set of genomic and epigenomic datasets, the authors identify clinically relevant super-enhancers amplified in ovarian cancer patients and functionally validate their activity.
- Michael R. Kelly
- , Kamila Wisniewska
- & Hector L. Franco
-
Article
| Open Access
Natural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity
Natural Killer cells are key mediators of anti-tumour immunosurveillance and anti-viral immunity. Here, the authors map regulatory genetic variation in primary Natural Killer cells, providing new insights into their role in human health and disease.
- James J. Gilchrist
- , Seiko Makino
- & Benjamin P. Fairfax
-
Article
| Open Access
Senescent cells limit p53 activity via multiple mechanisms to remain viable
To develop therapeutics that selectively eliminate pathological senescent cells it is important to understand their survival mechanisms. Here, the authors show that senescent cells manage to survive by keeping p53 activity in check through multiple mechanisms, including inhibitory mechanisms that involve p53 binding to ribonucleases.
- Ines Sturmlechner
- , Chance C. Sine
- & Jan M. van Deursen
-
Article
| Open Access
RNase III-CLASH of multi-drug resistant Staphylococcus aureus reveals a regulatory mRNA 3′UTR required for intermediate vancomycin resistance
Regulatory small RNA (sRNA) interact with mRNAs to regulate their stability, transcription, and translation via diverse mechanisms. Here, Mediati et al. apply RNase III-CLASH to multidrug-resistant Staphylococcus aureus to characterise the network of RNA–RNA interactions associated with RNase III and identify a regulatory mRNA 3′UTR, named vigR-3′UTR, involved in the regulation of genes relevant for vancomycin sensitivity.
- Daniel G. Mediati
- , Julia L. Wong
- & Jai J. Tree
-
Article
| Open Access
RIViT-seq enables systematic identification of regulons of transcriptional machineries
Here the authors present their method ‘regulon identification by in vitro transcription-sequencing’ (RIViT-seq), which enables systematic identification of target genes of transcription factors of interest. They applied RIViT-seq to 13 sigma factors from Streptomyces coelicolor A3(2) and successfully identified target genes of 11 of these, expanding the regulatory characterisation in this organism.
- Hiroshi Otani
- & Nigel J. Mouncey
-
Article
| Open Access
The impact of species-wide gene expression variation on Caenorhabditis elegans complex traits
Gene expression links genomic variation to organismal trait differences. Here, the authors identify regulatory loci underlying gene expression variation in C. elegans and demonstrate how this variation could impact other complex traits.
- Gaotian Zhang
- , Nicole M. Roberto
- & Erik C. Andersen
-
Article
| Open Access
Integrating 3D genomic and epigenomic data to enhance target gene discovery and drug repurposing in transcriptome-wide association studies
Transcriptome-wide association studies can be used to test the effects of predicted gene expression in a cohort of individuals based on genetic data. Here, the authors developed a transcriptome-wide association method that integrates 3D genomic and epigenomic data with expression quantitative trait loci to improve gene expression predictions.
- Chachrit Khunsriraksakul
- , Daniel McGuire
- & Dajiang J. Liu
-
Article
| Open Access
Dietary restriction and the transcription factor clock delay eye aging to extend lifespan in Drosophila Melanogaster
Circadian dysfunction is a potential driver of eye aging. Here the authors report that in conjunction with the core molecular clock transcription factor Clock, dietary restriction promotes rhythmic homeostatic mechanisms within photoreceptors to delay visual senescence and extend lifespan in Drosophila Melanogaster.
- Brian A. Hodge
- , Geoffrey T. Meyerhof
- & Pankaj Kapahi
-
Article
| Open Access
Differential regulation of alternative promoters emerges from unified kinetics of enhancer-promoter interaction
Alternative promoters differ in their expression patterns, whose mechanisms are not well understood. Here the authors show that alternative promoters of a Drosophila embryonic gene hunchback are regulated by different action modes of two enhancers.
- Jingyao Wang
- , Shihe Zhang
- & Heng Xu
-
Article
| Open Access
Activation of Xist by an evolutionarily conserved function of KDM5C demethylase
Here the authors show eutherian mammals co-opted the histone demethylase KDM5C during sex-chromosome evolution to induce X-chromosome inactivation by upregulating Xist expression selectively in females.
- Milan Kumar Samanta
- , Srimonta Gayen
- & Sundeep Kalantry
-
Article
| Open Access
Preventing erosion of X-chromosome inactivation in human embryonic stem cells
Cloutier et al. discover that human embryonic stem cells (hESCs) cultured with media containing inhibitors of GSK3 proteins undergo erosion of X-chromosome inactivation, which equalizes X-linked gene expression between females and males. The findings inform the faithful culture of hESCs.
- Marissa Cloutier
- , Surinder Kumar
- & Sundeep Kalantry
-
Article
| Open Access
Context-specific effects of sequence elements on subcellular localization of linear and circular RNAs
Ron and Ulitsky found using massively parallel assays that the effects of short RNA sequences on the subcellular localization of their host RNAs are strongly dependent on the host RNA form, linear or circular, and spliced or unspliced.
- Maya Ron
- & Igor Ulitsky
-
Article
| Open Access
Placental multi-omics integration identifies candidate functional genes for birthweight
The placenta plays key roles in fetal development and subsequent health. Here, the authors integrate placental methylation and transcriptome data with genetic loci associated with birthweight to identify functional genes underpinning fetal growth regulation.
- Fasil Tekola-Ayele
- , Xuehuo Zeng
- & Ronald Wapner
-
Article
| Open Access
A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation
Non-coding variants can regulate transcription factor binding and gene expression at variable chromatin modules. Here, the authors show that a germline variant induces transcription factor nucleation through chromatin compaction leading to AXIN2 up-regulation and is associated to better prognosis in chronic lymphocytic leukaemia.
- Gerard Llimos
- , Vincent Gardeux
- & Bart Deplancke
-
Article
| Open Access
Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF
Chromosome conformation capture (3 C) techniques have captured largescale 3D genome architecture. Here the authors present their “Tiled-MCC” approach for generation of 3 C data across megabase-scale loci at very high (up to 20 bp) resolution, which allowed them to observe nano-scale chromatin structures and investigate how these structures depend on cohesin and CTCF.
- Abrar Aljahani
- , Peng Hua
- & A. Marieke Oudelaar
-
Article
| Open Access
Multilayered regulations of alternative splicing, NMD, and protein stability control temporal induction and tissue-specific expression of TRIM46 during axon formation
The genetic control underlying axon formation in neurons is unknown. Here, the authors report that neural-specific induction of TRIM46, one of the earliest axonal markers, is regulated by alternative splicing, NMD, and protein stability controls.
- John K. Vuong
- , Volkan Ergin
- & Sika Zheng
-
Article
| Open Access
A hierarchy of biomolecular proportional-integral-derivative feedback controllers for robust perfect adaptation and dynamic performance
The design of feedback biomolecular controllers is essential to synthetically regulate biological processes in a robust and timely fashion. Here the authors introduce a wide array of biomolecular Proportional-Integral-Derivative (PID) controllers that are capable of enhancing stability and dynamic performance, and also reducing stochastic noise.
- Maurice Filo
- , Sant Kumar
- & Mustafa Khammash
-
Article
| Open Access
Multidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers
Alterations in cis-regulatory elements (CREs) can contribute to pancreatic diseases. Here the authors combine chromatin profiling and interaction points with in vivo reporter assays in zebrafish to uncover functionally equivalent human CREs, helping to predict disease-relevant enhancers.
- Renata Bordeira-Carriço
- , Joana Teixeira
- & José Bessa
-
Article
| Open Access
Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery
The functional effects of genetic loci associated with autoimmune disease are not well understood. By dissecting an autoimmune disease genetic locus, the authors define an immune cell-type-specific enhancer and the molecular mechanisms underlying the dysregulation of IRF8 expression by lupus risk variants.
- Tian Zhou
- , Xinyi Zhu
- & Nan Shen
-
Article
| Open Access
DNA sequence-dependent formation of heterochromatin nanodomains
The ability to predict epigenetic regulation is an important challenge in biology. Here the authors describe heterochromatin nanodomains (HNDs) and compare four different types of H3K9me2/3-marked HNDs in mouse embryonic stem cells. They further develop a computational framework to predict genome-wide HND maps from DNA sequence and protein concentrations, at single-nucleotide resolution.
- Graeme J. Thorn
- , Christopher T. Clarkson
- & Vladimir B. Teif
-
Article
| Open Access
Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology
Understanding regulation of genes associated to disease can reveal insights into disease mechanisms. Here, the authors perform an airway epithelial transcriptome-wide association analysis to elucidate genetic determinants of airway dysfunction in asthma, identifying genetic mechanisms of mucus pathobiology.
- Satria P. Sajuthi
- , Jamie L. Everman
- & Max A. Seibold
-
Article
| Open Access
Massively 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
-
Article
| Open Access
An RNA-binding protein acts as a major post-transcriptional modulator in Bacillus anthracis
HitRS is a two-component system that responds to cell envelope damage in the bacterium Bacillus anthracis. Here, the authors identify an RNA-binding protein that regulates HitRS function by modulating the stability of the hitRS mRNA. In addition, the protein binds to over 70 RNAs and affects the expression of genes involved in multiple cellular processes.
- Hualiang Pi
- , Andy Weiss
- & Eric P. Skaar
-
Article
| Open Access
Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia
‘Mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with poor clinical outcome, however, their impact on chromatin dynamics remains unexplored. Here the authors use a multi-omics approach for chronic myelomonocytic leukemia (CMML) and investigate the transcriptome and chromatin landscape of ASXL1MT CMML.
- Moritz Binder
- , Ryan M. Carr
- & Mrinal M. Patnaik
-
Article
| Open Access
The core and accessory Hfq interactomes across Pseudomonas aeruginosa lineages
Protein Hfq regulates bacterial mRNA translation and stability by interacting with mRNAs and small noncoding RNAs. Here, the authors identify Hfq-interacting RNAs in three strains representing major phylogenetic lineages of Pseudomonas aeruginosa, highlighting intra-species diversity in post-transcriptional regulatory networks.
- Julian Trouillon
- , Kook Han
- & Stephen Lory
-
Article
| Open Access
Arabidopsis RBV is a conserved WD40 repeat protein that promotes microRNA biogenesis and ARGONAUTE1 loading
MicroRNAs regulate gene expression through RNA cleavage or translation repression. Here the authors show that RBV, an evolutionarily conserved WD40 domain protein, acts to promote MIR transcription, pri-miRNA processing and miRNA loading into AGO1.
- Chao Liang
- , Qiang Cai
- & Xuemei Chen
-
Article
| Open Access
Xenogeneic 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
-
Article
| Open Access
A fast Myosin super enhancer dictates muscle fiber phenotype through competitive interactions with Myosin genes
The contractile properties of adult myofibers are shaped by their Myosin heavy chain isoform content. Here the authors show that a super enhancer controls the spatiotemporal expression of the genes at the fast myosin heavy chain locus by DNA looping and that this expression profile is recapitulated in a rainbow transgenic mouse model of the locus.
- Matthieu Dos Santos
- , Stéphanie Backer
- & Pascal Maire
-
Article
| Open Access
Dicer promotes genome stability via the bromodomain transcriptional co-activator BRD4
While RNA interference is conserved across species, small RNA pathways are very diverse. In this study, Gutbrod et al. find that non-canonical roles of Dicer in genome stability are in fact deeply conserved from yeast to humans.
- M. J. Gutbrod
- , B. Roche
- & R. A. Martienssen
-
Article
| Open Access
Genomic variants affecting homoeologous gene expression dosage contribute to agronomic trait variation in allopolyploid wheat
The connection between expression variation and phenotypic diversity in the populations of polyploid crops remains elusive. Here, the authors reveal the impact of genetic variants leading to biased expression of homoeologous genes in hexaploid wheat on agronomic traits.
- Fei He
- , Wei Wang
- & Eduard Akhunov
The hypoxia response pathway promotes PEP carboxykinase and gluconeogenesis in C. elegans