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| Open AccessActivator-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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Article
| Open AccessMulti-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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Article
| Open AccessCyclic AMP induces reversible EPAC1 condensates that regulate histone transcription
Spatial compartmentalization is central to nuclear function. Here, the authors demonstrate that EPAC1 can enter the nucleus and regulate the transcription of a histone cluster by forming biomolecular condensates in its proximity in response to cAMP.
- Liliana Felicia Iannucci
- , Anna Maria D’Erchia
- & Konstantinos Lefkimmiatis
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Article
| Open AccessStructural 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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Article
| Open AccessMLL-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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Article
| Open AccessRNAPII-dependent ATM signaling at collisions with replication forks
Deregulation of transcription by oncogenes leads to collisions of RNA Polymerase II (RNAPII) with DNA replication machinery (transcription-replication conflicts, TRCs). This study shows that RNAPII activates ATM kinase at TRCs providing a mechanism for replication fork stalling and ATM activation at TRCs.
- Elias Einig
- , Chao Jin
- & Nikita Popov
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Article
| Open AccessRedox 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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Article
| Open AccessHigh-sensitive nascent transcript sequencing reveals BRD4-specific control of widespread enhancer and target gene transcription
Here the authors reveal that high-sensitive nascent transcript sequencing provides an extended high-resolution view on transcription, including lowly transcribed enhancers. Widespread transcription at enhancers and their target genes depends on the BET family protein BRD4.
- Annkatrin Bressin
- , Olga Jasnovidova
- & Andreas Mayer
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Article
| Open AccessStructural basis for negative regulation of the Escherichia coli maltose system
MalY represses the E. coli maltose system by direct interaction with MalT that blocks its oligomerization. Maltotriose-binding leads to conformational remodelling of MalT and stabilizes the C-terminal domains required for downstream signalling.
- Yuang Wu
- , Yue Sun
- & Jijie Chai
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Article
| Open AccessStepwise modifications of transcriptional hubs link pioneer factor activity to a burst of transcription
Eukaryotic transcription involves the formation of subnuclear hubs that enrich transcriptional machinery. Here the authors show that the hubs undergo stepwise modifications to fuel a burst of transcription rather than having a stable composition.
- Chun-Yi Cho
- & Patrick H. O’Farrell
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Article
| Open AccessTRIM28 modulates nuclear receptor signaling to regulate uterine function
This paper identifies Tripartite motif-containing 28 (TRIM28) as a novel modulator of steroid hormone signaling. TRIM28 deficiency disrupts uterine cell functions and composition leading to fertility defects
- Rong Li
- , Tianyuan Wang
- & Francesco J. DeMayo
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Article
| Open AccessThe HSV-1 ICP22 protein selectively impairs histone repositioning upon Pol II transcription downstream of genes
Herpes simplex virus 1 (HSV-1) infection disrupts transcription termination by RNA Polymerase II. Here, Djakovic et al. identify the immediate-early protein ICP22 protein of HSV-1 to induce open chromatin downstream of genes upon read-through transcription involving the histone chaperone FACT.
- Lara Djakovic
- , Thomas Hennig
- & Lars Dölken
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Article
| Open AccessMultifactor 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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Article
| Open AccessMOF-mediated histone H4 Lysine 16 acetylation governs mitochondrial and ciliary functions by controlling gene promoters
Here the authors show that epigenetic regulation through the histone acetyltransferase MOF and the acetylation of histone H4 lysine 16 affect essential functions in the mitochondria and primary cilia. This regulation is important to promote epidermal differentiation and hair follicle formation.
- Dongmei Wang
- , Haimin Li
- & Rui Yi
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Article
| Open AccessMaternal TDP-43 interacts with RNA Pol II and regulates zygotic genome activation
Zygotic genome activation is crucial for mammalian embryonic development. Here, the authors find that TDP-43 is indispensable for mouse embryonic development and mediates zygotic genome activation through Pol II configuration.
- Xiaoqing Nie
- , Qianhua Xu
- & Lei Li
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Article
| Open AccessA model for organization and regulation of nuclear condensates by gene activity
Through a physics-based model framework, the authors propose a central role for the nonequilibrium processes underling gene activity in shaping morphology, dynamics, and regulation of diverse nuclear condensates.
- Halima H. Schede
- , Pradeep Natarajan
- & Krishna Shrinivas
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Article
| Open AccessSelective 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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Article
| Open AccessThe NAD salvage pathway in mesenchymal cells is indispensable for skeletal development in mice
Deficiency in NAD+ has been implicated in skeletal deformities during development in both humans and mice. Here, the authors use mice that lack the critical enzyme of the NAD+ salvage pathway Nampt in mesenchymal lineage cells to show that the NAD salvage pathway is indispensable for endochondral but not intramembranous bone development.
- Aaron Warren
- , Ryan M. Porter
- & Maria Almeida
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Article
| Open AccessChromatin 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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Article
| Open AccessTRIM5α recruits HDAC1 to p50 and Sp1 and promotes H3K9 deacetylation at the HIV-1 LTR
TRIM5α is known to restrict HIV-1 reverse transcription. Here, Ran et al. report that TRIM5α recruits HDAC1 to NF-κB p50, Sp1, and HIV-1 LTR, and promotes H3K9 deacetylation at the HIV-1 LTR, leading to TNFα-induced HIV-1 LTR-driven expression.
- Xiang-Hong Ran
- , Jia-Wu Zhu
- & Dan Mu
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Article
| Open AccessA 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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Article
| Open AccessM1BP is an essential transcriptional activator of oxidative metabolism during Drosophila development
The transcriptional regulation of mitochondrial oxidative phosphorylation gene expression is poorly understood. Using the developing Drosophila flight muscle, the authors identify the transcription factor M1BP as a new major regulator of this process.
- Gabriela Poliacikova
- , Marine Barthez
- & Andrew J. Saurin
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Article
| Open AccessTranscriptional 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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Article
| Open AccessThe conserved RNA-binding protein Seb1 promotes cotranscriptional ribosomal RNA processing by controlling RNA polymerase I progression
Ribosome biogenesis is influenced by the rate of RNAPI progression. Yet, mechanisms that control RNAPI elongation have remained elusive. Here, the authors show that the conserved protein Seb1 promotes cotranscriptional rRNA processing by controlling RNAPI progression.
- Maxime Duval
- , Carlo Yague-Sanz
- & François Bachand
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Article
| Open AccessThe NELF pausing checkpoint mediates the functional divergence of Cdk9
Promoter-proximal pausing by RNA Pol II is a key aspect of how gene expression is transcriptionally regulated in higher eukaryotes. Here the authors show that only NELF-mediated pausing enforces a strict early checkpoint for Cdk9 by efficiently shutting down gene transcription following loss of Cdk9.
- Michael DeBerardine
- , Gregory T. Booth
- & John T. Lis
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Article
| Open AccessDouble 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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Article
| Open AccessLung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling
Pulmonary fibrosis results from dysregulated lung repair, but the role of endothelial cells (EC) in fibrosis is unclear. Here, the authors show that FOXF1/R-Ras signalling in EC inhibits profibrotic mediators and that ECspecific nanoparticle FOXF1 gene therapy decreases lung fibrosis in mice.
- Fenghua Bian
- , Ying-Wei Lan
- & Tanya V. Kalin
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Article
| Open AccessDependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis
Transcriptional dysregulation contributes to tumor progression. Here the authors show that transcriptional complex NELF interacts with SLUG, and co-opts KAT2B, to promote the expression of epithelial-mesenchymal transition (EMT) and stemness-associated genes in breast cancer.
- Jieqiong Zhang
- , Zhenhua Hu
- & Wee-Wei Tee
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Article
| Open AccessTranscription 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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Article
| Open AccessBuffering 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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Article
| Open AccessStructural basis of Ty1 integrase tethering to RNA polymerase III for targeted retrotransposon integration
Cryo-EM structures of Ty1 integrase-Pol III complexes reveal determinants of Ty1 targeting upstream of Pol III-transcribed genes, and a functional impact of the integrase on Pol III activity that may increase the probability of Ty1 integration.
- Phong Quoc Nguyen
- , Sonia Huecas
- & Carlos Fernández-Tornero
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Article
| Open AccessThe RRM-mediated RNA binding activity in T. brucei RAP1 is essential for VSG monoallelic expression
Monoallelic VSG expression is essential for Trypanosoma brucei survival. Competition between TbRAP1’s RNA and dsDNA binding activities ensures that TbRAP1 sustains a high level expression of the active VSG while silencing other VSGs globally.
- Amit Kumar Gaurav
- , Marjia Afrin
- & Bibo Li
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Article
| Open AccessDynamic 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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Article
| Open AccessCvkR 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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Article
| Open AccessWidespread 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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Article
| Open AccessAngiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice
ACE inhibitors are widely used to treat cardiovascular diseases and promote angiogenesis. Here, the authors show a central role for endothelial USP7-Sp1/Sp3-Notch1 signalling in pathophysiological angiogenesis in response to ACE inhibitor treatment.
- Hanlin Lu
- , Peidong Yuan
- & Wencheng Zhang
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Article
| Open AccessA 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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Article
| 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