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| Open AccessLSD1/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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Article
| Open AccessStructural 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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Article
| Open AccessActive mRNA degradation by EXD2 nuclease elicits recovery of transcription after genotoxic stress
Here the authors show that the exonuclease EXD2 is involved in the recovery of class II gene transcription after UV irradiation. EXD2 travels from the mitochondria to the nucleus to interact with RNA Pol II and degrade new synthetized mRNA to allow transcription following DNA repair.
- Jérémy Sandoz
- , Max Cigrang
- & Frédéric Coin
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Article
| Open AccessA 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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Article
| Open AccessCoupled 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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Article
| Open AccessStructural basis of transcription recognition of a hydrophobic unnatural base pair by T7 RNA polymerase
T7 RNA polymerase (RNAP) is widely used for synthesizing RNA molecules with synthetic modifications and unnatural base pairs (UBPs). Here, authors show the structural basis of how UBPs are recognized as template and substrate, providing mechanistic insights into UBP transcription by T7 RNAP.
- Juntaek Oh
- , Michiko Kimoto
- & Dong Wang
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Article
| Open AccessTargeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation
Here the authors generate an RNA-based platform to neutralize the major epigenetic player DNMT1. Using this targeted approach, aberrant DNA methylation in cancer can be corrected.
- Carla L. Esposito
- , Ida Autiero
- & Annalisa Di Ruscio
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Article
| Open AccessSTREAMING-tag system reveals spatiotemporal relationships between transcriptional regulatory factors and transcriptional activity
Using the newly developed STREAMING-tag system, the authors find that clusters of RNA polymerase II and BRD4 are formed specifically in the transcriptionally active state near the Nanog gene in mouse embryonic stem cells.
- Hiroaki Ohishi
- , Seiru Shimada
- & Hiroshi Ochiai
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Article
| Open AccessGenetic 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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Article
| Open AccessERK-mediated NELF-A phosphorylation promotes transcription elongation of immediate-early genes by releasing promoter-proximal pausing of RNA polymerase II
Growth factor-induced release of RNA Pol-II promoter-proximal pausing is vital for immediate-early gene expression, but its mechanism remains elusive. Here, the authors reveal roles of ERK and PP2A in this process and their dysregulation in cancer.
- Seina Ohe
- , Yuji Kubota
- & Mutsuhiro Takekawa
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Article
| Open AccessAn 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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Article
| Open AccessThe PNUTS-PP1 complex acts as an intrinsic barrier to herpesvirus KSHV gene expression and replication
The PNUTS-PP1 complex directly binds to RNA, and interacts with polymerase II and RNA processing factors to control transcriptional elongation rates and slow polymerase II after polyadenylation sites to promote termination. Using a genome-wide CRISPR screen, Devlin et al. identify this complex as a critical suppressor of herpesvirus KSHV gene expression. They further provide evidence that PNUTS-PP1 controls elongation both downstream and upstream of polyadenylation sites on specific viral genes.
- Anne M. Devlin
- , Ashutosh Shukla
- & Nicholas K. Conrad
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Article
| Open AccessPPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response
The authors describe a functional crosstalk between the p53 network and the integrated stress response through the p53 repressor PPM1D. Inhibition of PPM1D potentiates p53-dependent transactivation and apoptosis via induction of the HRI-eIF2α-ATF4 pathway.
- Zdenek Andrysik
- , Kelly D. Sullivan
- & Joaquin M. Espinosa
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Article
| Open AccessStructural basis of RNA polymerase II transcription on the chromatosome containing linker histone H1
The mechanism by which RNAPII transcribes the DNA in the chromatosome with H1 has remained enigmatic. Here the authors present the cryo-EM structures of the RNAPII-chromatosome complexes, and explain how RNAPII is regulated by H1 in chromatin.
- Rina Hirano
- , Haruhiko Ehara
- & Hitoshi Kurumizaka
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Article
| Open AccessPPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation
Mutations in PPARγ lead to lipodystrophy, but the mechanisms by which the mutations affect the activity in chromatin is unknown. Here, Madsen, Broekema et al. showed that mutations affecting two intermolecular interactions compromise chromatin remodeling.
- Maria Stahl Madsen
- , Marjoleine F. Broekema
- & Eric Kalkhoven
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Article
| Open AccessDusp6 deficiency attenuates neutrophil-mediated cardiac damage in the acute inflammatory phase of myocardial infarction
Dusp6, an ERK specific phosphatase, was identified as a regenerative repressor during zebrafish heart regeneration. Here, the authors show that Dusp6 deficiency improves post infarctional cardiac repair by predominantly attenuating neutrophil-mediated myocardial damage in mammalian hearts.
- Xiaohai Zhou
- , Chenyang Zhang
- & Jing-Wei Xiong
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Article
| Open AccessOn-microscope staging of live cells reveals changes in the dynamics of transcriptional bursting during differentiation
Here the authors observe transcription dynamics in real-time throughout erythropoiesis by combining PP7 tagging of α-globin RNA transcripts and “on-microscope” cell staging. They show how the pattern of transcriptional bursting changes during differentiation, with variability in individual cells significantly reduced at the peak period of gene expression.
- D. M. Jeziorska
- , E. A. J. Tunnacliffe
- & D. R. Higgs
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Article
| Open AccessEnhancer 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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Article
| Open AccessFOXQ1 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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Article
| Open AccessRunx2 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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Article
| Open AccessMaintenance 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
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Article
| Open AccessInduction 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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Article
| Open AccessInositol hexakisphosphate is required for Integrator function
Integrator is a multi-subunit protein complex with roles in noncoding RNA 3′-end processing and mRNA transcription attenuation. Here, the authors reveal a conserved binding site for IP6 in the Integrator cleavage module and show that IP6 binding is required for Integrator function.
- Min-Han Lin
- , Madeline K. Jensen
- & Liang Tong
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Article
| Open AccessThe 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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Article
| Open AccessVAL1 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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Article
| Open AccessA small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II
The SMN protein recognizes symmetric dimethylarginine by its Tudor domain, and SMN deficiency leads to spinal muscular atrophy. Here, Liu et al. discover a small molecule that binds to the SMN Tudor domain and disrupts the interaction between SMN and RNA Polymerase II.
- Yanli Liu
- , Aman Iqbal
- & Jinrong Min
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Article
| Open AccessWRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome
Short stature is a hallmark of Werner Syndrome, but the underlying mechanisms are not well studied. Here they report that WRN regulates bone development and growth by opening SHOX-G-quadruplexes via its helicase activity both in vitro and in vivo.
- Yuyao Tian
- , Wuming Wang
- & Wai-Yee Chan
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Article
| Open AccessLiver group 2 innate lymphoid cells regulate blood glucose levels through IL-13 signaling and suppression of gluconeogenesis
Besides hepatocytes, resident immune cells of the liver are also contributing to the body’s energy homeostasis. Here authors show that group 2 innate lymphoid cells interact with a specific set of hepatocytes in suppressing gluconeogenesis and regulate blood glucose levels via Interleukin-13 signalling.
- Masanori Fujimoto
- , Masataka Yokoyama
- & Tomoaki Tanaka
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Article
| Open AccessCryptococcal 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
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Article
| Open AccessFunctional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis
Myofibroblasts contribute to the development of liver fibrosis. Here, the authors report that the transcription factor Basonuclin 2 (BNC2) integrates fibrogenic signals and drives myofibroblastic transcriptional activation in liver fibrosis.
- Marie Bobowski-Gerard
- , Clémence Boulet
- & Jérôme Eeckhoute
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Article
| Open AccessMTG8 interacts with LHX6 to specify cortical interneuron subtype identity
There is a large diversity of inhibitory interneurons in the mammalian cerebral cortex. How this emerges during embryogenesis remains unclear. Here, the authors identify MTG8 as a co-factor of LHX6 and a new regulator of cortical interneuron development.
- Zeinab Asgarian
- , Marcio Guiomar Oliveira
- & Nicoletta Kessaris
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Article
| Open AccessTaz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity
Immune system function declines with age, a consequence of defects in hematopoietic stem cells (HSCs). Here the authors show that TAZ buffers age-related loss of PU.1 activity to maintain HSC functionality and identify the surface protein Clca3a1 as a marker of “young-like” HSCs, even in old mice.
- Kyung Mok Kim
- , Anna Mura-Meszaros
- & Björn von Eyss
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Article
| Open AccessThe TFEB-TGIF1 axis regulates EMT in mouse epicardial cells
Epithelial-mesenchymal transition (EMT) is a complex process involved in organogenesis. Here, the authors show that the transcription factor EB (TFEB) regulates EMT in epicardium during heart development by tuning sensitivity to TGFβ signaling.
- Elena Astanina
- , Gabriella Doronzo
- & Federico Bussolino
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Article
| Open AccessAutomated model-predictive design of synthetic promoters to control transcriptional profiles in bacteria
Transcription rates are regulated by the interactions between RNA polymerase, sigma factor, and promoter DNA sequences in bacteria. Here the authors combine massively parallel experiments & machine learning to develop a predictive biophysical model of transcription, validated across 22132 bacterial promoters, and apply it to the design and debugging of genetic circuits.
- Travis L. LaFleur
- , Ayaan Hossain
- & Howard M. Salis
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Article
| Open AccessSingle-cell transcriptome and translatome dual-omics reveals potential mechanisms of human oocyte maturation
Development of methods for simultaneous single cell analysis of transcription and translation is still underway. Here, Hu et al. develop single-cell transcriptome and translatome dual-omics on human oocytes, which enables them to identify OOSP2 as an induction factor during human oocyte maturation.
- Wenqi Hu
- , Haitao Zeng
- & Kehkooi Kee
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Article
| Open AccessSpecificity of the Hox member Deformed is determined by transcription factor levels and binding site affinities
Despite the central role of Hox genes in controlling morphogenesis, the DNA binding of different Hox members is relatively similar. Here they show that specificity of Hox member Dfd relies on a precise balance of transcription factors and binding site affinities.
- Pedro B. Pinto
- , Katrin Domsch
- & Ingrid Lohmann
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Article
| Open AccessCK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis
Hippo signalling is often deregulated in cancers. Here the authors show that CK2 enhances the cooperation of HHEX with YAP-TEAD complex to promote colorectal tumorigenesis.
- Yuegui Guo
- , Zhehui Zhu
- & Chen-Ying Liu
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Article
| Open AccessStructural analysis of Red1 as a conserved scaffold of the RNA-targeting MTREC/PAXT complex
Unwanted RNA transcripts are targeted for degradation by nuclear complexes such as MTREC/PAXT. Here, the authors structurally and functionally characterized three interfaces of the scaffold protein Red1, providing mechanistic insights into conserved features of MTREC/PAXT architecture.
- Anne-Emmanuelle Foucher
- , Leila Touat-Todeschini
- & Jan Kadlec
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Article
| Open AccessA single WNT enhancer drives specification and regeneration of the Drosophila wing
The wing is a remarkable evolutionary novelty in insects. Here the authors demonstrate that the specification and regenerative capacity of the wing relies on a single wing-specific enhancer of the wingless gene in Drosophila.
- Elena Gracia-Latorre
- , Lidia Pérez
- & Marco Milán
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Article
| Open AccessVisualizing molecular interactions that determine assembly of a bullet-shaped vesicular stomatitis virus particle
Vesicular stomatitis virus (VSV) is the most widely studied prototype for negative-sense RNA viruses. Structure determination of VSV particles is particularly challenging because they are polymorphic with different helical symmetries. Here, Jenni et al. apply computational classification approaches to sort different morphologies, and obtain CryoEM reconstructions at 3.5–4.1 A resolution. They show that the matrix protein (M) is present in the virion in two layers, of which the inner layer associates with N protein of vRNPs.
- Simon Jenni
- , Joshua A. Horwitz
- & Stephen C. Harrison
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Article
| Open AccessStructural basis of transcriptional regulation by a nascent RNA element, HK022 putRNA
HK022 put is an RNA element that inhibits transcription termination without aids from protein factors. Here, authors solved cryo-EM structures of put-associated RNA polymerase and showed the structure of putRNA and its binding to the RNA polymerase.
- Seungha Hwang
- , Paul Dominic B. Olinares
- & Jin Young Kang
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Article
| Open AccessThe SWI/SNF chromatin remodeling factor DPF3 regulates metastasis of ccRCC by modulating TGF-β signaling
The functional role of DPF3, a component of the SWI/SNF chromatin remodelling complex associated with clear cell renal cell carcinoma (ccRCC), remains unknown. Here, the authors characterise the mechanism by which DPF3 promotes metastasis via the activation of the TGF-β signalling pathway in ccRCC.
- Huanhuan Cui
- , Hongyang Yi
- & Wei Chen
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Article
| Open AccessMettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a
m6A is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. Here the authors show a role for Mettl3-mediated RNA m6A modification in postnatal liver development by regulating the Hnf4a-centered transcriptional network
- Yan Xu
- , Zhuowei Zhou
- & Qi Zhang
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Article
| Open AccessInteraction between transcribing RNA polymerase and topoisomerase I prevents R-loop formation in E. coli
In E. coli, disruption of TopoI and RNAP interaction decreases cells viability and leads to hypernegative DNA supercoiling and R loops accumulation. TopoI and DNA gyrase bind around transcription units and TopoI recognizes cleavage sites by a specific motif and negative supercoiling.
- Dmitry Sutormin
- , Alina Galivondzhyan
- & Konstantin Severinov
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Article
| Open AccessXist exerts gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis
Here the authors investigate the functional relevance of X-chromosome inactivation (XCI) regulator Xist in hematopoiesis. They find that Xist loss leads to changes in the ratio of hematopoietic progenitor cells and results in chromatin accessibility and transcriptional upregulation on the inactive X chromosome, including XCI escape genes known to be associated with cell cycle and immune response.
- Tianqi Yang
- , Jianhong Ou
- & Eda Yildirim
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Article
| Open AccessCDK9 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
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Article
| Open AccessTargeting transcription in heart failure via CDK7/12/13 inhibition
In this study, Hsu et al. show that inhibition of CDK7/12/13 attenuates maladaptive transcriptional activation in cultured cardiomyocytes and a mouse model of heart failure, suggesting that targeting the transcription machinery might be a therapeutic approach to treat heart failure with reduced ejection fraction.
- Austin Hsu
- , Qiming Duan
- & Saptarsi M. Haldar
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Article
| Open AccessCohesin couples transcriptional bursting probabilities of inducible enhancers and promoters
Here the authors show inducible genes and enhancers are regulated mainly by transcriptional burst frequency and that this is coordinated in single cells and individual alleles. Cohesin, which is important for inducible gene expression, is largely dispensable for regulating enhancer burst frequencies; however, it is required for coupling burst frequencies of inducible enhancers and promoters.
- Irene Robles-Rebollo
- , Sergi Cuartero
- & Matthias Merkenschlager
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Article
| Open AccessEtv2 regulates enhancer chromatin status to initiate Shh expression in the limb bud
The embryonic limb bud is known to be patterned by a Shh morphogen gradient, though how Shh expression is activated remains less clear. Here the authors show that Etv2 acts as a pioneer transcription factor to mediate accessibility of the ZRS enhancer and initiate Shh expression.
- Naoko Koyano-Nakagawa
- , Wuming Gong
- & Daniel J. Garry