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Cis-regulatory interfaces reveal the molecular mechanisms underlying the notochord gene regulatory network of Ciona
The notochord is an essential hallmark of the chordate phylum. Here, Negrón-Piñeiro et al. study the notochord gene regulatory network in Ciona, and their findings illustrate how notochord transcription factors are coordinated by Brachyury and Foxa2.
- Lenny J. Negrón-Piñeiro
- , Yushi Wu
- & Anna Di Gregorio
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| Open Access
Transcription-driven DNA supercoiling counteracts H-NS-mediated gene silencing in bacterial chromatin
Proteins compacting the bacterial chromosome obstruct transcription and must be transiently displaced to allow gene expression. Here, the authors show that the bacterial nucleoid structuring protein H-NS can be dislodged, from a distance, by the twisting in the DNA generated ahead of approaching RNA polymerase.
- Nara Figueroa-Bossi
- , Rocío Fernández-Fernández
- & Lionello Bossi
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Diindoles produced from commensal microbiota metabolites function as endogenous CAR/Nr1i3 ligands
Here, combining metabolomic, proteomic and biophysical analyses, the authors identify and characterize a series of diindole molecules produced from commensal bacteria metabolites that act as specific agonists for the orphan constitutive androstane receptor (CAR), having potential to modulate gut and liver inflammation, metabolic diseases and cancer.
- Jiabao Liu
- , Ainaz Malekoltojari
- & Henry M. Krause
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Reciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer
TP63 is a master regulator transcription factor in squamous cell carcinomas (SCCs). Here the authors report that TP63 suppresses IFNγ signaling in SCC tumors and that its inhibition is associated with enhanced anti-tumor immunity and response to anti-PD1.
- Yuan Jiang
- , Yueyuan Zheng
- & Yan-Yi Jiang
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Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
Metastasis arises from disseminated tumour cells (DTCs) while the underlying mechanism of DTCs plasticity remains underexplored. Here, the authors show that spatially organized oncogenic enhancers on chromatin sustain the establishment of retinoic acid (RA)-stimulated transcriptional memory through activation of SOX9, supporting the escape of quiescent DTCs from NK-mediated immune surveillance.
- Daniela Michelatti
- , Sven Beyes
- & Alessio Zippo
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Fibroblast-specific PRMT5 deficiency suppresses cardiac fibrosis and left ventricular dysfunction in male mice
Epigenetic mechanisms play a key role in cardiac fibrosis associated with heart failure. Here, the authors show that protein arginine methyltransferase 5 (PRMT5), an epigenetic writer, regulates fibrotic gene transcription through histone methylation in mice.
- Yasufumi Katanasaka
- , Harumi Yabe
- & Tatsuya Morimoto
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The Deinococcus protease PprI senses DNA damage by directly interacting with single-stranded DNA
Lu et al. show that single-stranded DNA produced as a result of DNA damage may directly activate PprI in Deinococcus species, triggering the DNA damage response.
- Huizhi Lu
- , Zijing Chen
- & Yuejin Hua
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Predicting DNA structure using a deep learning method
In this work, the authors report a deep learning method, Deep DNAshape, to predict the influence of flanking regions on three-dimensional DNA structure and in structural readout mechanisms of protein-DNA binding.
- Jinsen Li
- , Tsu-Pei Chiu
- & Remo Rohs
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G-quadruplexes promote the motility in MAZ phase-separated condensates to activate CCND1 expression and contribute to hepatocarcinogenesis
G-quadruplexes (G4s) can recruit transcription factors to activate genes. Here, the authors revealed that G4s drive molecular motility in phase-separated condensates of MAZ and coactivators, leading to activated CCND1 expression in liver cancer.
- Wenmeng Wang
- , Dangdang Li
- & Guangchao Sui
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ANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation
The transcriptional program controlling the activation of cancer-associated fibroblasts (CAFs) remains to be elucidated. Here, the authors identify ANKRD1 as a mesenchymal-specific driver of CAF activation under negative direct control of androgen receptor, triggering AP-1 transcription factor complex activation.
- Luigi Mazzeo
- , Soumitra Ghosh
- & G. Paolo Dotto
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Article
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Mutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD
Intronic GGGGCC repeat expansion in the C9orf72 gene causes ALS/FTD. Here the authors show that mutant GGGGCC RNA triggers YY1-Fuzzy transcriptional dysregulation which subsequently induces Wnt/β-catenin pathway and activates cell death in C9ALS/FTD.
- Zhefan Stephen Chen
- , Mingxi Ou
- & Ho Yin Edwin Chan
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MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting
SKP2 is an oncogenic E3-ubiquitin ligase. Here the authors show that SKP2 is epigenetically regulated by the muscle lineage transcription factor MYOD, supports tumorigenesis in the Fusion Negative (FN) subtype of rhabdomyosarcoma (RMS) and impairs differentiation promoting degradation of p57Kip2.
- Silvia Pomella
- , Matteo Cassandri
- & Rossella Rota
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ERK2-topoisomerase II regulatory axis is important for gene activation in immediate early genes
Topoisomerase II (TOP2) has been identified as one of the regulators for the transcriptional activation of immediate early genes IEGs. Here the authors report that ERK1 and ERK2 oppositely regulate transcription and ERK2 regulates TOP2B-DNA interaction and catalysis to favor IEG transcription.
- Heeyoun Bunch
- , Deukyeong Kim
- & Shun-ichi Sekine
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Transposable element-initiated enhancer-like elements generate the subgenome-biased spike specificity of polyploid wheat
The direct impacts of transposable element dynamics on polyploid regulation and developmental specificity remain unclear. Here, the authors show that a large proportion of enhancer-like elements (ELEs) are mainly originated from RLG_famc7.3 specifically expanded in subgenome A, producing active nascent transcripts and influencing wheat spike development.
- Yilin Xie
- , Songbei Ying
- & Yijing Zhang
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Transcriptional responses of cancer cells to heat shock-inducing stimuli involve amplification of robust HSF1 binding
The authors compare the heat shock response between different cell lines and stimuli and reveal the genome-wide binding of its master transcription factor HSF1 as a platform for context-specific transcription activation.
- Sayantani Ghosh Dastidar
- , Bony De Kumar
- & Sergei Nechaev
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Themis2 regulates natural killer cell memory function and formation
Innate immunity represents the first line of defence against pathogens, but certain innate cells are capable of memory formation, albeit with different and lesser-known mechanisms than adoptive immune cells. Here authors show that Themis2 regulates both memory NK cell development and function, via distinct downstream pathways.
- Tsukasa Nabekura
- , Elfira Amalia Deborah
- & Akira Shibuya
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Transcriptional reprogramming by mutated IRF4 in lymphoma
Cancer is often associated with mutant transcription factors (TFs) but their functional characterization is challenging. Here, the authors describe a recurrent mutation within TF IRF4 in human lymphomas and they show how it causes a complex switch in TF specificity and functionality.
- Nikolai Schleussner
- , Pierre Cauchy
- & Stephan Mathas
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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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Activator-blocker model of transcriptional regulation by pioneer-like factors
How gene expression timing is regulated during development remains a key area of research. Here they show that zebrafish genome activators Pou5f3 and Nanog block each other’s activity on the enhancers of differentiation genes, preventing their premature expression.
- Aileen Julia Riesle
- , Meijiang Gao
- & Daria Onichtchouk
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Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries
Most mammalian TAD boundaries, which separate functional chromosomal domains, bind the CTCF protein. Here, the authors identify multi-level clustering of CTCF binding sites at TAD boundaries and confirm their individual contribution to TAD formation.
- Li-Hsin Chang
- , Sourav Ghosh
- & Daan Noordermeer
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Structural convergence endows nuclear transport receptor Kap114p with a transcriptional repressor function toward TATA-binding protein
Nuclear transport receptors mediate nucleocytoplasmic transport, collectively termed karyopherin-β (Kap-β) in yeast. Here, the authors present a cryo-EM structure of Kap114p, one of the Kap-βs, revealing a non-canonical function beyond nuclear transport that modulates yTBP-dependent transcription.
- Chung-Chi Liao
- , Yi-Sen Wang
- & Kuo-Chiang Hsia
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MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia
Previous studies have reported MLL-AF4 binding at intragenic and intergenic enhancers, however, the role of MLL-AF4 in enhancer function remains to be investigated. Here, the authors show that MLL-AF4 cooperates with PAF1 and FACT at enhancers to promote high-density interactions with oncogene promoters in leukemia.
- Nicholas T. Crump
- , Alastair L. Smith
- & Thomas A. Milne
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Redox driven B12-ligand switch drives CarH photoresponse
CarH is a bacterial B12-binding photoreceptor involved in transcriptional regulation. Here, the authors provide insights into B12 dynamics and associated cobalt redox changes following light activation. These demonstrate the CarH response integrates light and oxygen sensing.
- Harshwardhan Poddar
- , Ronald Rios-Santacruz
- & David Leys
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Multifactor transcriptional control of alternative oxidase induction integrates diverse environmental inputs to enable fungal virulence
Metabolic flexibility allows fungi to invade hostile niches. Here, Liu et al. dissect the molecular mechanisms by which Candida albicans upregulates virulence-enabling alternative oxidase expression in response to host-relevant respiratory stresses.
- Zhongle Liu
- , Pauline Basso
- & Leah E. Cowen
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Selective binding of retrotransposons by ZFP352 facilitates the timely dissolution of totipotency network
During zygotic genome activation the embryo must re-wire the regulatory network that sustains totipotency earlier during development. Here they identify ZFP352 as an essential factor that targets retrotransposon families to facilitate dissolution of the totipotency network and enable ZGA.
- Zhengyi Li
- , Haiyan Xu
- & Hongqing Liang
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Chromatin remodeling by Pol II primes efficient Pol III transcription
Transcription of RNA polymerase II is coupled with remodeling of chromatin. This study reports that transcription of RNA polymerase II is also required to prime and maintain nucleosome depletion at RNA polymerase III loci.
- Carlo Yague-Sanz
- , Valérie Migeot
- & Damien Hermand
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A multiple super-enhancer region establishes inter-TAD interactions and controls Hoxa function in cranial neural crest
The authors discovered a far distant genomic region containing multiple clusters of regulatory elements that drive coordinated Hoxa expression across chromatin topologically associating domains in cranial neural crest, and are required for patterning of facial structures.
- Sandra Kessler
- , Maryline Minoux
- & Filippo M. Rijli
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Transcriptional coactivation by EHMT2 restricts glucocorticoid-induced insulin resistance in a study with male mice
Glucocorticoids are known to induce insulin resistance via transcriptional activation of genes related to liver gluconeogenesis and insulin resistance. Here the authors report that in male mice treated with glucocorticoids, the transcriptional co-regulator EHMT2 is involved in the induction of Irs2 (a gene promoting insulin action) to restrict the extent of insulin resistance in the liver.
- Rebecca A. Lee
- , Maggie Chang
- & Jen-Chywan Wang
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Double DAP-seq uncovered synergistic DNA binding of interacting bZIP transcription factors
Here, the authors describe a new method to study how some proteins work together to control gene activity. They show that certain protein pairs can recognize new DNA sequences that they can’t recognize individually and control a wider range of genes.
- Miaomiao Li
- , Tao Yao
- & Shao-shan Carol Huang
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Transcription factor binding site orientation and order are major drivers of gene regulatory activity
Gene regulatory grammar remains difficult to decipher, hindering our ability to link genotype to phenotype. Here they use massively parallel reporter assays to test over 200,000 synthetic sequences, finding that transcription factor binding site order and orientation have a major effect on gene regulatory activity.
- Ilias Georgakopoulos-Soares
- , Chengyu Deng
- & Nadav Ahituv
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| Open Access
Buffering of transcription rate by mRNA half-life is a conserved feature of Rett syndrome models
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the transcriptional modulator MECP2. Here, the authors measured transcription rate and mRNA half-life changes in RTT patient-derived neurons to show transcription rate buffered by mRNA half-life changes.
- Deivid C. Rodrigues
- , Marat Mufteev
- & James Ellis
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Dynamic interplay between non-coding enhancer transcription and gene activity in development
Non-coding transcription at the intergenic regulatory regions is a prevalent feature of metazoan genomes, but its function remains uncertain. Here the authors show that enhancer function is flexibly tunable through the modulation of hub formation via surrounding non-coding transcription.
- Kota Hamamoto
- , Yusuke Umemura
- & Takashi Fukaya
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CvkR is a MerR-type transcriptional repressor of class 2 type V-K CRISPR-associated transposase systems
RNA-guided, CRISPR-associated transposons hold great promise for precision genome editing. Here, the authors provide genetic, biochemical and structural data how their activity is regulated in situ by CvkR, an unusual MerR family regulator.
- Marcus Ziemann
- , Viktoria Reimann
- & Wolfgang R. Hess
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Widespread perturbation of ETS factor binding sites in cancer
Few cancer drivers in non-coding regions have been identified so far. Here, the authors develop a transcription factor-aware burden test to predict non-coding variants and analyze the impact on transcription factor binding - especially ETS factors - as well as their impact on transcriptional activity.
- Sebastian Carrasco Pro
- , Heather Hook
- & Juan Ignacio Fuxman Bass
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A CpG island-encoded mechanism protects genes from premature transcription termination
Here the authors discover that SET1 complexes function as transcription anti-termination factors that bind to CpG islands and protect low to moderately transcribed genes from the pervasive termination activity of the ZC3H4 complex.
- Amy L. Hughes
- , Aleksander T. Szczurek
- & Robert J. Klose
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LSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice
Here, Prakasam and colleagues show that polyQ-expanded androgen receptor toxicity can be attenuated using artificial miRNAs targeting Lsd1 and Prmt6, two AR-co-activators overexpressed in an androgen-dependent manner specifically in skeletal muscle, thus ameliorating spinal-bulbar muscular atrophy phenotypes in flies and mice.
- Ramachandran Prakasam
- , Angela Bonadiman
- & Maria Pennuto
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Structural mechanism of BRD4-NUT and p300 bipartite interaction in propagating aberrant gene transcription in chromatin in NUT carcinoma
BRD4-NUT’s bipartite binding and activation of p300 in NUT carcinoma nucleates a feed-forward spread of histone hyperacetylation and chromatin condensation that sustains aberrant pro-proliferation gene transcription and perpetual tumor cell growth.
- Di Yu
- , Yingying Liang
- & Lei Zeng
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| Open Access
A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification
Defining cis-regulatory elements is an important goal in understanding how gene expression is regulated. Here the authors show blood cell-specific gene expression is controlled by the action of thousands of differentiation stage-specific sets of cis-elements that respond to cytokine signals terminating at signaling responsive transcription factors.
- B. Edginton-White
- , A. Maytum
- & C. Bonifer
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| Open Access
Coupled induction of prophage and virulence factors during tick transmission of the Lyme disease spirochete
The alternative sigma factor RpoS of Borrelia burgdorferi regulates a pathway implicated in tick transmission, mammalian infectivity and persistent infection. Here, the authors characterise the role of the RpoS negative regulator bbd18 and show that RpoS also controls induction of endogenous prophage.
- Jenny Wachter
- , Britney Cheff
- & Patricia A. Rosa
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| Open Access
Genetic manipulation of the human gut bacterium Eggerthella lenta reveals a widespread family of transcriptional regulators
Eggerthella lenta is a prominent human gut bacterium implicated in several physiological processes, but its study has remained limited. Here, by developing a genetic toolbox for E. lenta, the authors provide insights into how the bacterium regulates drug and dietary compound metabolism.
- Xueyang Dong
- , Ben G. H. Guthrie
- & Emily P. Balskus
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| Open Access
An NKX-COUP-TFII morphogenetic code directs mucosal endothelial addressin expression
Vascular addressins control lymphocyte homing, thus regulating immunity and inflammation, but how addressin expression is patterned remains unknown. Here the authors identify composite DNA elements (NCCEs) that bind NKX2 homeodomain proteins cooperatively with COUP-TFII to define a morphogenetic code that targets transcription of mucosal vascular addressins.
- Thanh Theresa Dinh
- , Menglan Xiang
- & Eugene C. Butcher
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| Open Access
Transposable elements orchestrate subgenome-convergent and -divergent transcription in common wheat
How subgenome-divergent and -convergent transcription is mediated and harmonized in hexaploid common wheat genome remains unclear. Here, via characterizing the cistrome maps, the authors reveal that transposon elements with transcription factor binding ability have the potential to make the contribution.
- Yuyun Zhang
- , Zijuan Li
- & Yijing Zhang
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Article
| Open Access
Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity
The role of enhancer de-regulation in anti-tumor immunity remains to be explored. Here, the authors suggest that ablation of MLL3 and MLL4, two enhancer-associated H3K4 monomethyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response.
- Hanhan Ning
- , Shan Huang
- & Deqing Hu
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| Open Access
FOXQ1 recruits the MLL complex to activate transcription of EMT and promote breast cancer metastasis
Forkhead box transcription factor, FOXQ1 is reported to promote epithelial-mesenchymal transition (EMT) and cancer metastasis. Here the authors show that FOXQ1 recruits the KMT2/MLL histone methyltransferase complex as a transcriptional coactivator to activate EMT programme in breast cancer.
- Allison V. Mitchell
- , Ling Wu
- & Guojun Wu
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| Open Access
Runx2 and Runx3 differentially regulate articular chondrocytes during surgically induced osteoarthritis development
Possible distinct contributions of Runx 2 and Runx3 in osteoarthritis have not been clarified. Nagata et al. show that Runx3 protects adult articular cartilage by extracellular matrix protein production in normal conditions, while Runx2 exerts both catabolic and anabolic effects during inflammation.
- Kosei Nagata
- , Hironori Hojo
- & Taku Saito
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| Open Access
Induction of the hepatic aryl hydrocarbon receptor by alcohol dysregulates autophagy and phospholipid metabolism via PPP2R2D
Alcohol consumption promotes neutral fat accumulation in the liver. Here, the authors report that alcohol induces aryl hydrocarbon receptor AhR in the liver, and hepatocyte-specific AhR deletion protects against alcohol induced accumulation potentially via transcriptional regulation of Protein phosphatase 2 regulatory subunit Bdelta and subsequent effects on autophagy.
- Yun Seok Kim
- , Bongsub Ko
- & Sang Geon Kim
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| Open Access
The transcriptional coactivator RUVBL2 regulates Pol II clustering with diverse transcription factors
RNA polymerase II (Pol II) transcription factories play a central role in gene expression and 3D chromatin organization. Here, the authors demonstrate that RUVBL2 directly regulates Pol II clustering at active gene promoters.
- Hui Wang
- , Boyuan Li
- & Xiong Ji
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| Open Access
VAL1 acts as an assembly platform co-ordinating co-transcriptional repression and chromatin regulation at Arabidopsis FLC
Cold-induced silencing of Arabidopsis FLC requires the binding of VAL1 to an intronic motif. Here, the authors show that ASAP and PRC1, two interacting partner complexes of VAL1, mediate co-transcriptional repression and chromatin modulation to effectively co-ordinate different steps in FLC silencing.
- Pawel Mikulski
- , Philip Wolff
- & Caroline Dean
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| Open Access
Cryptococcal Hsf3 controls intramitochondrial ROS homeostasis by regulating the respiratory process
Mitochondrial quality control prevents accumulation of intramitochondrial reactive oxygen species (mtROS), thus protecting cells against DNA damage. Here, Gao et al. show that an atypical heat shock factor responds to intramitochondrial stresses and regulates mtROS homeostasis in the pathogenic fungus Cryptococcus neoformans.
- Xindi Gao
- , Yi Fu
- & Chen Ding
Concerted transformation of a hyper-paused transcription complex and its reinforcing protein