Featured
-
-
Article
| Open AccessFuzzy recognition by the prokaryotic transcription factor HigA2 from Vibrio cholerae
Here, the authors dissect the fuzzy interaction between the prokaryote transcription factor HigA2 and its DNA target and show that specific, transient interactions drive specificity despite HigA2 remaining mostly disordered.
- San Hadži
- , Zala Živič
- & Remy Loris
-
Article
| Open AccessCold-induced FOXO1 nuclear transport aids cold survival and tissue storage
How tissues adapt to extreme cold is not well understood. Here, the authors discover a mechanism that promotes FOXO1-mediated cold survival gene transcription at low temperatures, with potential implications for long-term tissue storage for transplantation.
- Xiaomei Zhang
- , Lihao Ge
- & Jingxing Ou
-
Article
| Open AccessMolecular switching in transcription through splicing and proline-isomerization regulates stress responses in plants
Transcription factor DREB2A interacts with Med25 to regulate stress responses. Here, the authors show that DREB2A uses splicing and proline-isomerization for this regulation and that proline cis-trans switching introduces structural frustration facilitating regulator exchange.
- Frederik Friis Theisen
- , Andreas Prestel
- & Karen Skriver
-
Article
| Open AccessUSP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress
Targeting ribosome biogenesis with the ribosome inhibitor, homoharringtonine (HHT), is effective in leukaemia but not in solid tumours. Here, the authors demonstrate that in solid tumours, activation of JNK signaling following HHT-induced ribosomal stress promotes Snail1 accumulation in the nucleolus which facilitates ribosome biogenesis and resistance to HHT.
- Kewei Qin
- , Shuhan Yu
- & Yong Yi
-
Article
| Open AccessTrim33 masks a non-transcriptional function of E2f4 in replication fork progression
Here the authors show that under replicative stress the E2f4 transcription factor recruits the Recql DNA helicase to facilitate DNA replication. The Trim33 ubiquitin ligase targets E2f4 to limit its interactions with Recql and chromatin.
- Vanessa Rousseau
- , Elias Einig
- & Nikita Popov
-
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
-
Article
| Open AccessA cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates
Here, the authors show that cell internalization of Engrailed2 not only relies on its homeodomain, but also involves a cationic region which interacts selectively with cell surface heparan sulfates.
- Sébastien Cardon
- , Yadira P. Hervis
- & Sandrine Sagan
-
Article
| Open AccessEnhancement of a prime editing system via optimal recruitment of the pioneer transcription factor P65
Prime editing represents a great advance to the genome editing field but is currently limited by the editing efficiency. Here the authors look to improve the efficiency by recruiting target proteins and show that the transcription factor P65 could enhance the desired editing outcomes at different gene loci.
- Ronghao Chen
- , Yu Cao
- & Xueli Zhang
-
Article
| Open AccessStructural basis of human SNAPc recognizing proximal sequence element of snRNA promoter
This study presenting the cryo-EM structure of human SNAPc in complex with U6-1 PSE, significantly enforces our understanding of the mechanism of the SNAPc assembly, the PSE-specific recognition by SNAPc and the PIC assembly on U6 snRNA promoter.
- Jianfeng Sun
- , Xue Li
- & Wei Wang
-
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
-
Article
| Open AccessSystematic 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 AccessChromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA
Here the authors used single-molecule imaging and manipulation to study the mechanical effects of transcription factor Sox2 co-condensation with DNA and chromatin. They found that Sox2 condensates exert a high level of mechanical stress on DNA, but this stress is dramatically attenuated by nucleosomes assembled on the DNA.
- Tuan Nguyen
- , Sai Li
- & Shixin Liu
-
Article
| Open AccessOpposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer
While many treatments for prostate cancer suppress the androgen receptor it becomes reactivated during disease progression. Here, the authors show that a KLF5 transcriptional programme is also activated during treatment and promotes migration and the appearance of a basal cell phenotype.
- Meixia Che
- , Aashi Chaturvedi
- & Scott M. Dehm
-
Article
| Open AccessLiquid condensation of reprogramming factor KLF4 with DNA provides a mechanism for chromatin organization
KLF4, OCT4, SOX2 and MYC cooperate to reorganize chromatin during somatic cell reprogramming. Here the authors show that KLF4 forms a liquid-like biomolecular condensate that recruits OCT4 and SOX2, and that condensation of the isolated KLF4 DNA binding domain with DNA is enhanced by CpG methylation
- Rajesh Sharma
- , Kyoung-Jae Choi
- & Josephine C. Ferreon
-
Article
| Open AccessEpistasis shapes the fitness landscape of an allosteric specificity switch
Epistasis plays an important role in the evolution of novel protein functions because it determines the mutational path a protein takes. Here, the authors combine functional, structural and biophysical analyses to characterize epistasis in a computationally redesigned ligand-inducible allosteric transcription factor and found that epistasis creates distinct biophysical and biological functional landscapes.
- Kyle K. Nishikawa
- , Nicholas Hoppe
- & Srivatsan Raman
-
Article
| Open AccessYeast cell fate control by temporal redundancy modulation of transcription factor paralogs
How dynamic transcription factors temporally interact to regulate stress survival in yeast is currently unclear. Here the authors integrate single-cell imaging, RNA-seq, and modeling to identify a new cell fate control mechanism mediated by temporal redundancy modulation during yeast stress response.
- Yan Wu
- , Jiaqi Wu
- & Yihan Lin
-
Article
| Open AccessAndrogen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly
Androgen receptor (AR) signaling is regulated by multiple post-translational modifications. Here, the authors identify the writer and reader enzymes for AR ADP-ribosylation and show how they modulate AR signaling output in prostate cancer cells.
- Chun-Song Yang
- , Kasey Jividen
- & Bryce M. Paschal
-
Article
| Open AccessMulti-omics analysis reveals contextual tumor suppressive and oncogenic gene modules within the acute hypoxic response
The response to hypoxia can significantly impact oncogenic processes. Here, the authors define the early transcriptional response to acute hypoxia and identify HIF1A target genes as part of this acute response, providing a resource for investigating context-dependent roles of HIF1A in the biology of cancer.
- Zdenek Andrysik
- , Heather Bender
- & Joaquin M. Espinosa
-
Article
| Open AccessGenetically encoded formaldehyde sensors inspired by a protein intra-helical crosslinking reaction
In order to understand the role of formaldehyde in living systems, real-time monitoring is required. Here the authors report a genetically encoded, reaction-based formaldehyde sensor (FAsor) that enables visualisation of formaldehyde in mammalian cells and tissues.
- Rongfeng Zhu
- , Gong Zhang
- & Peng R. Chen
-
Article
| Open AccessStructural basis for nuclear import selectivity of pioneer transcription factor SOX2
The SOX2 pioneer transcription factor performs critical roles in pluripotency and self-renewal of embryonic stem cells. Here the authors show that SOX2’s two nuclear localization signal sequences form a contiguous binding interface on the nuclear import receptor importin-α3, and provide a structural basis for the preference of SOX2 binding to IMPα3.
- Bikshapathi Jagga
- , Megan Edwards
- & Jade K. Forwood
-
Article
| Open AccessTBPL2/TFIIA complex establishes the maternal transcriptome through oocyte-specific promoter usage
The vertebrate TATA-binding protein (TBP) paralogue (TBPL2) is only expressed in growing oocytes, where TBP is absent. Here the authors highlight a unique role for the TBPL2/TFIIA complex in the establishment of the oocyte transcriptome by using a specific TSS recognition code.
- Changwei Yu
- , Nevena Cvetesic
- & László Tora
-
Article
| Open AccessThe δ subunit and NTPase HelD institute a two-pronged mechanism for RNA polymerase recycling
The bacterial helicase-like transcription factor HelD interacts with the RNA polymerase (RNAP) and together with the RNAP δ subunit enhances RNAP cycling. Here, the authors present the cryo-EM structures of the monomeric and dimeric Bacillus subtilis RNAP-δ-HelD complexes and suggest a model for HelD/δ-mediated RNAP recycling and putative hibernation.
- Hao-Hong Pei
- , Tarek Hilal
- & Markus C. Wahl
-
Article
| Open AccessSelective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains
STAT3 is an attractive therapeutic target but its homology with other STAT proteins complicates the development of selective inhibitors. Here, the authors develop monobodies with high affinity and selectivity for STAT3 and show that they can interfere with cellular STAT3 activity.
- Grégory La Sala
- , Camille Michiels
- & Oliver Hantschel
-
Article
| Open AccessThe Sox2 transcription factor binds RNA
Some transcription factors have been proposed to functionally interact with RNA to facilitate proper regulation of gene expression. Here the authors demonstrate that human Sox2 interact directly and with high affinity to RNAs through its HMG DNA-binding domain.
- Zachariah E. Holmes
- , Desmond J. Hamilton
- & Robert T. Batey
-
Article
| Open AccessDual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance
The transcription factor Aire mediates tissue-specific antigen expression in the thymus for T cell central tolerance induction. Here the authors show that Aire, via its CARD domain, forms multimers that can misdirect Aire to PML bodies leading to the loss of Aire transcriptional activity and induction of autoimmunity.
- Yu-San Huoh
- , Bin Wu
- & Sun Hur
-
Article
| Open AccessMulti-level and lineage-specific interactomes of the Hox transcription factor Ubx contribute to its functional specificity
Many transcription factors regulate gene expression in a lineage- and process-specific manner, despite being expressed in several cell types. Here, the authors show that the Hox transcription factor Ubx has lineage-specific interactomes, which contribute to its cell context-dependent functions.
- Julie Carnesecchi
- , Gianluca Sigismondo
- & Ingrid Lohmann
-
Article
| Open AccessChaperone-mediated ordered assembly of the SAGA and NuA4 transcription co-activator complexes in yeast
Transcription initiation involves the coordinated assembly and activity of large multimeric complexes. Here the authors report on the chaperone-mediated ordered assembly of the SAGA and NuA4 transcription co-activator complexes in fission yeast, providing insight into the de novo assembly of transcriptional complexes and the contribution of dedicated chaperones to this process.
- Alberto Elías-Villalobos
- , Damien Toullec
- & Dominique Helmlinger
-
Article
| Open AccessStructure and functional implications of WYL domain-containing bacterial DNA damage response regulator PafBC
The transcriptional activator PafBC is a regulator of mycobacterial DNA damage response and upregulates genes involved in DNA repair. Here, the authors present the crystal structure of Arthrobacter aurescens PafBC and suggest that PafBC might be activated by binding of a nucleic acid ligand, and bioinformatics analysis shows that its central WYL domain is a widespread feature in bacterial transcription factors.
- Andreas U. Müller
- , Marc Leibundgut
- & Eilika Weber-Ban
-
Article
| Open AccessPituitary cell translation and secretory capacities are enhanced cell autonomously by the transcription factor Creb3l2
Pituitary POMC secreting cells achieve high hormone expression levels after birth but the mechanism for this regulation is unclear. Here, the authors show that this process is driven cell autonomously by the differentiation factor Tpit that activates the bZIP transcription factors Creb3l2 and XBP1 to enhance translation and secretory capacities.
- Konstantin Khetchoumian
- , Aurélio Balsalobre
- & Jacques Drouin
-
Article
| Open AccessIn situ structures of rotavirus polymerase in action and mechanism of mRNA transcription and release
Rotaviruses are of great medical significance because they cause gastroenteritis in children. Here the authors provide insights into the mechanism of viral mRNA transcription by determining the in situ cryo-EM structures of a working rotavirus’ RNA-dependent-RNA polymerase, which is of interest for antiviral drug design.
- Ke Ding
- , Cristina C. Celma
- & Z. Hong Zhou
-
Article
| Open AccessCrystal structure of human Mediator subunit MED23
Mediator is a large multi-subunits complex essential to the regulation of transcription by RNA pol II. Here the authors report the crystal structure of MED23—one of the largest subunits of the complex together with MED1 and MED14—revealing a complex architecture and filling an important gap in the structural characterization of Mediator.
- Didier Monté
- , Bernard Clantin
- & Vincent Villeret
-
Article
| Open AccessStructural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1
Incessant telomere synthesis in cancer cells depends on specific mutations in the TERT promoter, enabling its activation by transcription factors ETS1 and p52. Here, the authors elucidate the structural basis for p52/ETS1 binding to mutant TERT, suggesting a general mechanism for TERT reactivation in cancer.
- Xueyong Xu
- , Yinghui Li
- & Haiwei Song
-
Article
| Open AccessThe MerR-like protein BldC binds DNA direct repeats as cooperative multimers to regulate Streptomyces development
BldC regulates the onset of differentiation in Streptomycetes by a yet unknown molecular mechanism. Using a combination of structural, biochemical and in vivo approaches, the authors show that BldC controls the transcription of several developmental regulators and unravel its DNA binding mode.
- Maria A. Schumacher
- , Chris D. den Hengst
- & Mark J. Buttner
-
Article
| Open AccessKSHV episomes reveal dynamic chromatin loop formation with domain-specific gene regulation
Genomic loops and their temporal dynamics play an important role in gene expression of DNA viruses, but are incompletely understood. Here, the authors use capture Hi-C analyses and identify genomic architectural dynamics of KSHV that are regulated by the viral transactivator K-Rta.
- Mel Campbell
- , Tadashi Watanabe
- & Yoshihiro Izumiya
-
Article
| Open AccessStructure of a Wbl protein and implications for NO sensing by M. tuberculosis
Mycobacterium tuberculosis WhiB1 is a DNA-binding protein with a NO sensitive [4Fe-4S] cluster. Here the authors present the NMR structure of WhiB1 and suggest how loss of the iron-sulfur cluster through nitrosylation affects WhiB1 DNA binding and leads to transcriptional reprogramming.
- Bassam K. Kudhair
- , Andrea M. Hounslow
- & Jeffrey Green
-
Article
| Open AccessNon-canonical activation of OmpR drives acid and osmotic stress responses in single bacterial cells
OmpR is a transcription factor activated in acid and osmotic responses of Gram-negative bacteria, leading to acidification of the bacterial cytoplasm. Here the authors use single cell pH imaging to define the role of OmpR-regulated genes in the acidification response to osmotic and acid stress of Salmonella and E. coli.
- Smarajit Chakraborty
- , Ricksen S. Winardhi
- & Linda J. Kenney
-
Article
| Open AccessThe multiple antibiotic resistance operon of enteric bacteria controls DNA repair and outer membrane integrity
Transcription factors MarR and MarA confer multidrug resistance in enteric bacteria by modulating efflux pump and porin expression. Here, Sharma et al. show that MarA also upregulates genes required for lipid trafficking and DNA repair, thus reducing antibiotic entry and quinolone-induced DNA damage.
- Prateek Sharma
- , James R. J. Haycocks
- & David C. Grainger
-
Article
| Open AccessThe Pu.1 target gene Zbtb11 regulates neutrophil development through its integrase-like HHCC zinc finger
Neutrophils are increased in response to injury and infection but how they form from a common granulocyte-macrophage progenitor is unclear. Here, the authors identify a role for the transcriptional repressor ZBTB11 in zebrafish, which is regulated by master myeloid regulators and repressesTP53.
- Maria-Cristina Keightley
- , Duncan P. Carradice
- & Graham J. Lieschke
-
Article
| Open AccessA genetic cell context-dependent role for ZEB1 in lung cancer
ZEB1 is a driver of epithelial-to-mesenchymal transition that usually promotes lung cancer in the context of KRAS mutation. Here, the authors uncover a growth suppressive role for ZEB1 in EGFRmutant lung adenocarcinoma, thus elucidating the context dependent function of this protein.
- Ting Zhang
- , Lixia Guo
- & Yanan Yang
-
Article
| Open AccessThe anti-sigma factor RsrA responds to oxidative stress by reburying its hydrophobic core
Counteracting oxidative stress is essential in all organisms. Here, the authors outline a mechanism used by actinomycete bacteria in which oxidation of zinc-binding RsrA blocks its interaction with σR by sequestering hydrophobic residues used to bind σRwithin its own core.
- Karthik V. Rajasekar
- , Konrad Zdanowski
- & Colin Kleanthous
-
Article
| Open AccessSREBP1c-CRY1 signalling represses hepatic glucose production by promoting FOXO1 degradation during refeeding
The clock protein Cry regulates hepatic glucose metabolism. Here the authors show that SREBP1c, activated by insulin signalling after feeding, directly regulates Cry transcription at specific circadian time points, and that Cry represses hepatic glucose production by promoting proteasomal degradation of Foxo1.
- Hagoon Jang
- , Gha Young Lee
- & Jae Bum Kim
-
Article
| Open AccessMYC/MIZ1-dependent gene repression inversely coordinates the circadian clock with cell cycle and proliferation
The circadian clock and the cell cycle systems coordinate global physiology. Here the authors show that MYC represses the clock genes, together with MIZ1, and induces proliferation, suggesting that MYC inversely modulates cell cycle and circadian clock genes.
- Anton Shostak
- , Bianca Ruppert
- & Michael Brunner
-
Article
| Open AccessA threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development
NFATc1 orchestrates thymocyte development. Here the authors show that NFATc1 expression is regulated by distinct promoters during thymocyte differentiation, and by conditional deletion of individual promoters in mice they define their specific roles in the control of T-cell development by NFATc1.
- Stefan Klein-Hessling
- , Ronald Rudolf
- & Amiya Kumar Patra
-
Article
| Open AccessSuspension survival mediated by PP2A-STAT3-Col XVII determines tumour initiation and metastasis in cancer stem cells
Tumour initiating cells (TICs) are anoikis resistant in suspension culture and they are critical for initiating tumorigenesis in vivo. Here, the authors show that these features are promoted by hemidesmosome-like structures enriched in laminin V and collagen XVII 5 upregulated in TICs by phospho-STAT3 whose levels are increased through PP2A inactivation.
- Chen-Chi Liu
- , Shih-Pei Lin
- & Shih-Chieh Hung
-
Article
| Open AccessGenome editing in butterflies reveals that spalt promotes and Distal-less represses eyespot colour patterns
Transcription factors Distal-less(Dll) and spalt were co-opted during the evolution of butterfly eyespots. Here, Zhang and Reed use CRISPR/Cas9 genome editing to show that while spalt is a positive regulator of eyespots as predicted, Dll knockouts have positive effects on both eyespot size and number, thus suggesting that Dllis an eyespot repressor, not an activator as previously thought.
- Linlin Zhang
- & Robert D. Reed
-
Article
| Open AccessA splicing isoform of TEAD4 attenuates the Hippo–YAP signalling to inhibit tumour proliferation
The Hippo/Yap signalling pathway is found deregulated in several cancers. Here, the authors uncover an additional mechanism of YAP regulation that occurs via alternately spliced isoform of TEAD4, which acts as a dominant negative regulator of YAP-TEAD signalling.
- Yangfan Qi
- , Jing Yu
- & Zefeng Wang
-
Article
| Open AccessZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation
The t(8;21) translocation is often found in acute myeloid leukaemia but is not sufficient for development of the disease. In this study, the authors identify frequent mutations in the transcriptional repressor, ZBTB7A, in these patients and show that the mutations reduce DNA binding activity.
- Luise Hartmann
- , Sayantanee Dutta
- & Philipp A. Greif
-
Article
| Open AccessFasting induces a subcutaneous-to-visceral fat switch mediated by microRNA-149-3p and suppression of PRDM16
Visceral adiposity is associated with metabolic diseases, whereas subcutaneous adiposity is comparatively benign. Here, the authors report that subcutaneous adipose tissue adopts visceral-like characteristics in response to prolonged fasting, and show this is mediated by miR-149-3p and its target, PRDM16.
- Hanying Ding
- , Shasha Zheng
- & Xiaohong Jiang
-
Article
| Open AccessThe elongation factor Spt5 facilitates transcription initiation for rapid induction of inflammatory-response genes
A subset of inflammatory-response NF-κB target genes is activated immediately after proinflammatory stimulation. Here, the authors show that in rapidly induced genes, depletion of the elongation factor Spt5 reduces transcription initiation and TFIID–promoter association without affecting the transcription elongation rate.
- Gil Diamant
- , Anat Bahat
- & Rivka Dikstein