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| Open AccessThe pRb/RBL2-E2F1/4-GCN5 axis regulates cancer stem cell formation and G0 phase entry/exit by paracrine mechanisms
Cancer stem cells (CSCs) are associated with chemoresistance and poor prognosis in multiple cancer types. Here, the authors investigate the role of secreted Wnt ligands in pancreatic and breast CSCs and identify E2F1/4-GCN5-pRb/RBL2 as a regulatory axis underlying Wnt secretion.
- Chao-Hui Chang
- , Feng Liu
- & Siim Pauklin
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Article
| Open AccessEfficient gene knockout and genetic interaction screening using the in4mer CRISPR/Cas12a multiplex knockout platform
Paralog synthetic lethals have been assessed with multiple CRISPR-based methods, but systematic comparison among these platforms is unavailable. Here, the authors systematically compare combinatorial perturbation platforms and establish the in4mer CRISPR/Cas12a multiplex knockout platform.
- Nazanin Esmaeili Anvar
- , Chenchu Lin
- & Traver Hart
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Article
| Open AccessLSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice
Even though glucocorticoids are potent anti-inflammatory agents, they can cause muscle wasting. Here, the authors show that targeting the glucocorticoid receptor coactivator LSD1 limits muscle loss without reducing the drugs’ efficiency on the immune system.
- Qingshuang Cai
- , Rajesh Sahu
- & Delphine Duteil
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Article
| Open AccessHBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription
The regulatory mechanism and functional consequence of lysine lactylation remain to be explored. Here, the authors identify HBO1 as a lysine lactyltransferase and suggest a potential role of HBO1 in tumorigenesis through H3K9la-mediated transcription regulation.
- Ziping Niu
- , Chen Chen
- & Kai Zhang
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Article
| Open AccessOxygen enhances antiviral innate immunity through maintenance of EGLN1-catalyzed proline hydroxylation of IRF3
Oxygen is an essential requirement for aerobic organisms. Here the authors explore the role of oxygen in the antiviral innate response in multiple models of infection and suggest oxygen enhances the antiviral innate response via EGLN1 hydroxylation of IRF3.
- Xing Liu
- , Jinhua Tang
- & Wuhan Xiao
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Article
| Open AccessPersistent TFIIH binding to non-excised DNA damage causes cell and developmental failure
Hereditary nucleotide excision repair deficiencies cause different cancerous and progeroid disorders of which the exact etiology is not understood. This study finds that prolonged binding of DNA repair factor TFIIH to DNA damage contributes to a more severe phenotype caused by DNA repair deficiency.
- Alba Muniesa-Vargas
- , Carlota Davó-Martínez
- & Hannes Lans
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Article
| Open AccessChromosome organization shapes replisome dynamics in Caulobacter crescentus
Whether bacterial replisome progression follows a “factory” or “track” model remains a long-standing controversy. Here, the authors find that cells can switch between the two models, in a process governed by dynamic chromosome organization processes.
- Chen Zhang
- , Asha Mary Joseph
- & Suliana Manley
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Article
| Open AccessFlexible TAM requirement of TnpB enables efficient single-nucleotide editing with expanded targeting scope
Here the authors report that a thermophilic archaeal TnpB enables efficient gene editing in the natural host: they see that the TnpB has different TAM requirements for eliciting cell death and for facilitating gene editing. They show that TnpB can be harnessed for flexible single-nucleotide editing with templated repair.
- Xu Feng
- , Ruyi Xu
- & Qunxin She
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Article
| Open AccessCoCas9 is a compact nuclease from the human microbiome for efficient and precise genome editing
Cas9 nucleases hold clinical significance for genome editing therapies. Here the authors characterize CoCas9, a compact, efficient and precise Cas9 from the human microbiome, and show that delivery via AAV vectors enables efficient editing in the mouse retina, expanding the genome editing toolbox.
- Eleonora Pedrazzoli
- , Michele Demozzi
- & Anna Cereseto
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Article
| Open AccessTyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity
Coactivator-associated arginine methyltransferase 1 (CARM1) is an important target in hematologic malignancies. In this work, the authors show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates CARM1 which regulates its methyltransferase activity and alters its target specificity.
- Hidehiro Itonaga
- , Adnan K. Mookhtiar
- & Stephen D. Nimer
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Article
| Open Accesshoxc12/c13 as key regulators for rebooting the developmental program in Xenopus limb regeneration
During organ regeneration, gene expression patterns similar to those in normal development are reestablished. Here, Kawasumi-Kita et al. explore core rebooting factors that operate during Xenopus limb regeneration. Their results indicate that hoxc12 and hoxc13 are critical for reactivating tissue growth.
- Aiko Kawasumi-Kita
- , Sang-Woo Lee
- & Yoshihiro Morishita
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Article
| Open AccessDetecting m6A at single-molecular resolution via direct RNA sequencing and realistic training data
Direct RNA-seq offers the possibility to identify RNA modifications on single molecules. Here, the authors report on the synthesis of biologically realistic training data and the development of mAFiA that accurately detects m6A on single read level.
- Adrian Chan
- , Isabel S. Naarmann-de Vries
- & Christoph Dieterich
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Article
| Open AccessTracing genetic diversity captures the molecular basis of misfolding disease
Pei et al. applied Gaussian process-based machine learning to capture dynamic spatial covariance relationships managed by proteostasis to mediate cooperative folding on a residue basis as a standard model for precision disease management.
- Pei Zhao
- , Chao Wang
- & William E. Balch
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Article
| Open AccessThe DEAD-box ATPase Dbp10/DDX54 initiates peptidyl transferase center formation during 60S ribosome biogenesis
Cruz et al. describe the role of Dbp10/DDX54 in remodeling rRNA structure within the immature eukaryotic peptidyl transferase center of the ribosome, coupling energy-dependent catalysis to a post-catalytic role in factor exchange during 60S ribosomal subunit assembly.
- Victor E. Cruz
- , Christine S. Weirich
- & Jan P. Erzberger
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Article
| Open AccessPhysiological DNA damage promotes functional endoreplication of mammary gland alveolar cells during lactation
Breastfeeding confers lifelong benefits to both mother and child, yet women worldwide experience lactation insufficiency. Here, the authors show that DNA damage occurring in the breast during pregnancy drives the generation of milk-producing cells.
- Rut Molinuevo
- , Julien Menendez
- & Lindsay Hinck
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Article
| Open AccessHost response during unresolved urinary tract infection alters female mammary tissue homeostasis through collagen deposition and TIMP1
Urinary tract infections (UTIs) can elicit systemic host-responses. Here the authors report that, in a mouse model, unresolved UTI is associated with alterations of the mammary tissue, including collagen deposition and hyperplasia.
- Samantha Henry
- , Steven Macauley Lewis
- & Camila Oresco dos Santos
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Article
| Open AccessA fine-scale Arabidopsis chromatin landscape reveals chromatin conformation-associated transcriptional dynamics
Plants utilize transcriptional dynamics to adapt to cold stress. Here, Zhang et al. describe a network of chromatin interactions between gene promoters across the Arabidopsis genome that could facilitate co-regulation of gene expression during cold stress.
- Yueying Zhang
- , Qianli Dong
- & Huakun Zhang
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Article
| Open AccessInsights into the inhibition of protospacer integration via direct interaction between Cas2 and AcrVA5
Here, the authors characterize an anti-CRISPR protein that prevents protospacer integration by Cas1-Cas2, providing structural insights that may benefit CRISPR-Cas systems research.
- Mingfang Bi
- , Wenjing Su
- & Xiaobing Mo
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Article
| Open AccessReciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry
Unveiling the regulation of mitotic protein degradation is crucial for cancer therapy. Here, the authors reveal that a reciprocal inhibition of PIN1-APC/CCDH1 controls the cell cycle and mitotic protein degradation, offering a synergistic anti-tumor strategy.
- Shizhong Ke
- , Fabin Dang
- & Kun Ping Lu
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Article
| Open AccessSm-like protein Rof inhibits transcription termination factor ρ by binding site obstruction and conformational insulation
Said et al. used cryoEM, biochemistry and bioinformatics to uncover how the Sm-like protein Rof regulates transcription termination. Rof binds termination factor ρ, inhibiting ρ ring closure and its association with RNA or transcription complexes.
- Nelly Said
- , Mark Finazzo
- & Markus C. Wahl
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Article
| Open AccessDynamics of DNA damage-induced nuclear inclusions are regulated by SUMOylation of Btn2
Maintaining a healthy nuclear proteome during DNA damage is important but its regulation is poorly understood. The authors here show that a SUMO modification of the small heat shock protein Btn2 regulates yeast nuclear protein sequestration during stress.
- Arun Kumar
- , Veena Mathew
- & Peter C. Stirling
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Article
| Open AccessReciprocating RNA Polymerase batters through roadblocks
During transcription, RNA polymerases may encounter protein roadblocks along template DNA. Here, Qian et al. use magnetic tweezers to show that RNA polymerases can backtrack and ram into longer lived roadblocks to transit through them.
- Jin Qian
- , Allison Cartee
- & Laura Finzi
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Article
| Open AccessIntegrated proteogenomic and metabolomic characterization of papillary thyroid cancer with different recurrence risks
Papillary thyroid cancers (PTC) generally have good prognosis, but their recurrence rate remains high. Here, the authors use proteogenomics and metabolomics to identify molecular features in PTC tumours and determine PTC subtypes that are associated with prognosis and potential targeted therapies.
- Ning Qu
- , Di Chen
- & Rongliang Shi
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Article
| Open AccessRegulation by the RNA-binding protein Unkempt at its effector interface
How RNA-binding proteins (RBPs) regulate gene expression via effectors of RNA processing is unclear. Here, the authors dissect the effector interface of an essential RBP, Unkempt, and investigate its contribution to translational control in cells.
- Kriti Shah
- , Shiyang He
- & Jernej Murn
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Article
| Open AccessPathogenic mutations of human phosphorylation sites affect protein–protein interactions
Here the authors characterise the impact of phosphorylation site mutations in intrinsically disordered regions (IDRs) on protein-protein interactions, highlighting the critical role of phosphorylation of IDRs in health and disease.
- Trendelina Rrustemi
- , Katrina Meyer
- & Matthias Selbach
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Article
| Open AccessPRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects
PRPF8 is a hotspot for mutations causing retinitis pigmentosa-type 13. Here the authors generated PRPF8 patient-specific retinal cells, demonstrating an important role for this splicing factor in spliceosome kinetics and 5’ splice site selection.
- Robert Atkinson
- , Maria Georgiou
- & Majlinda Lako
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Article
| Open AccessNardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer
Polo-like kinase 3 (Plk3) has a tumor suppressive role through the induction of apoptosis, however, the mechanism underlying its activation is unclear. Here, in pancreatic cancer, the authors show that activation of Plk3 is dependent on its cleavage into p41Plk3, by the metalloendopeptidase nardilysin.
- Jie Fu
- , Jianhua Ling
- & Paul J. Chiao
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Article
| Open AccessCell-type-specific mRNA transcription and degradation kinetics in zebrafish embryogenesis from metabolically labeled single-cell RNA-seq
This study analyzes the embryonic replacement of maternally contributed mRNA with new mRNA in single cells and shows dynamic spatio-temporal regulation of maternal mRNA decay and cell-type specific retention within the earliest specified cell types in zebrafish embryos.
- Lior Fishman
- , Avani Modak
- & Michal Rabani
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Article
| Open AccessSingle-cell and spatial RNA sequencing reveal the spatiotemporal trajectories of fruit senescence
Fruit senescence is a complex physiological process. Here, the authors construct a single-cell expression atlas of pitaya pericarp pitaya to provide a spatiotemporal perspective of the dynamic process of plant senescence.
- Xin Li
- , Bairu Li
- & Robert Henry
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Article
| Open AccessDNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues
Analysis of 92 human homeodomain mutants, including disease-associated variants and variants of uncertain significance, reveals variants with altered DNA binding affinity and/or specificity and specificity-determining positions.
- Kian Hong Kock
- , Patrick K. Kimes
- & Martha L. Bulyk
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Article
| Open AccessAn Intricate Network Involving the Argonaute ALG-1 Modulates Organismal Resistance to Oxidative Stress
In this study, Vergani-Junior et al. show that increased expression of the argonaute ALG-1 in long-lived worms improves oxidative stress resistance through the modulation of microRNAs that downregulate the protein disulfide isomerase pathway.
- Carlos A. Vergani-Junior
- , Raíssa De P. Moro
- & Marcelo A. Mori
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Article
| Open AccessConcerted transformation of a hyper-paused transcription complex and its reinforcing protein
Here, authors use cryoEM, biochemistry and molecular dynamics simulations to delineate a functional cycle of RfaH, a universally conserved transcription factor that undergoes a fold-switch during recruitment to the transcribing RNA polymerase.
- Philipp K. Zuber
- , Nelly Said
- & Stefan H. Knauer
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Article
| Open AccessCis-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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Article
| Open Accessp53 promotes revival stem cells in the regenerating intestine after severe radiation injury
The tumor suppressor p53 is the guardian of the genome. Here, the authors use comprehensive approaches to demonstrate that transient p53 activity induces revival stem cells to promote the regeneration of severely irradiated intestinal epithelium in mice.
- Clara Morral
- , Arshad Ayyaz
- & David G. Kirsch
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Article
| Open AccessAccelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation
Here the authors find that erythroblasts of myelodysplastic syndromes with SF3B1 mutation leading to inefficient erythropoiesis show DNA replication stress with accelerated forks and reduced R-loops. Restoring R-loops by a histone deacetylase inhibitor rescues erythroid differentiation.
- David Rombaut
- , Carine Lefèvre
- & Michaela Fontenay
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Article
| Open AccessSystematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis
Authors perform an in vivo mass spectrometry-based interactome analysis of HOIL-1-interacting protein, a key component of linear ubiquitination assembly complex.
- Yesheng Fu
- , Lei Li
- & Lingqiang Zhang
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Article
| Open AccessSeeding the meiotic DNA break machinery and initiating recombination on chromosome axes
Meiotic cells deliberately break their DNA to allow chromosomes to swap genetic material. Here, authors reveal genetically separable pathways controlling the seeding and growth of chromosome-bound protein condensates responsible for DNA breaks.
- Ihsan Dereli
- , Vladyslav Telychko
- & Attila Tóth
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Article
| Open AccessNon-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells
DNA methylation is an essential epigenetic mark in mammals. The maintenance of this mark relies on two key proteins: DNMT1 and UHRF1. Here the authors show that, beyond activating DNMT1, UHRF1 has crucial regulatory functions in cancer cells.
- Kosuke Yamaguchi
- , Xiaoying Chen
- & Pierre-Antoine Defossez
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Article
| Open AccessTranslation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations
An emerging therapeutic strategy is to suppress nonsense mutations with engineered suppressor tRNAs. Here, the authors show that the mRNA translation velocity is a key parameter determining the efficacy of suppressor tRNAs.
- Nikhil Bharti
- , Leonardo Santos
- & Zoya Ignatova
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Article
| Open AccessStatins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1
Endothelial dysfunction has been shown to occur in HFpEF and we know that statins can target endothelial dysfunction by inhibiting miR-133a. Here the authors show that statins improve diastolic dysfunction in HFpEF by increasing the levels of a circRNA which, in turns, binds to miR-133a modulating its downstream targets.
- Bin Li
- , Wen-Wu Bai
- & Shuang-Xi Wang
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Article
| Open AccessThe CRISPR-Cas13a Gemini System for noncontiguous target RNA activation
CRISPR-Cas13a based methods currently use contiguous target RNA activation, which only enables single-target detection or editing. Here the authors propose a noncontiguous target RNA activation approach which can provide rapid, simultaneous and sensitive detection of two RNAs in a single readout, as well as parallel dual transgene knockdown.
- Hongrui Zhao
- , Yan Sheng
- & Jiaming Hu
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Article
| Open AccessDbf4-dependent kinase promotes cell cycle controlled resection of DNA double-strand breaks and repair by homologous recombination
The repair of DNA double strand breaks is strictly controlled during the cell cycle by the CDK kinase. Here the authors identify the DDK kinase as a second major regulator for this cell cycle regulation and elucidate its functional targets.
- Lorenzo Galanti
- , Martina Peritore
- & Boris Pfander
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Article
| Open AccessLoss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment
CREBBP and KMT2D mutations frequently co-occur in B cell lymphomas with unclear significance. Here the authors show that they cooperate to skew B cell fate decisions and induce a CD8-depleted immune-evasive microenvironment to facilitate lymphomagenesis.
- Jie Li
- , Christopher R. Chin
- & Ari M. Melnick
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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
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Article
| Open AccessPatchy and widespread distribution of bacterial translation arrest peptides associated with the protein localization machinery
Regulatory arrest peptides interact with the bacterial ribosome to halt their own translation. Here, Fujiwara et al. analyse thousands of bacterial genome sequences and identify additional arrest peptides, revealing sequence diversity and patchy, but widespread, distribution across the bacterial domain.
- Keigo Fujiwara
- , Naoko Tsuji
- & Shinobu Chiba
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Article
| Open AccessPARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress
Here the authors show that PARP2 drives telomere fragility by orchestrating the Break-induced replication (BIR) pathway. This promotes DNA end resection and DNA synthesis via the regulation of POLD3.
- Daniela Muoio
- , Natalie Laspata
- & Elise Fouquerel
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Article
| Open AccessInvolution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway
Aging, chronic high-fat diet feeding, or housing at thermoneutrality induces brown adipose tissue (BAT) involution. Here, the authors demonstrate that physiologic aging induced involution and thermogenic dysfunction result from pyroptotic signalling activation.
- Xiaofan Yu
- , Gabrielle Benitez
- & Daorong Feng
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Article
| Open AccessLoss-of-function mutation in PRMT9 causes abnormal synapse development by dysregulation of RNA alternative splicing
Mutations in protein arginine methyltransferase 9 (PRMT9) are linked to intellectual disability. Here, the authors show that mutant PRMT9 fails to methylate its primary substrate SF3B2, causing aberrant RNA splicing and abnormal synapse development.
- Lei Shen
- , Xiaokuang Ma
- & Yanzhong Yang
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Article
| Open AccessThe PTM profiling of CTCF reveals the regulation of 3D chromatin structure by O-GlcNAcylation
CTCF, which is known to play critical role in chromatin structure, undergoes post-translational modifications (PTMs). In this research, O-GlcNAcylation was found to inhibit CTCF binding, impacting 3D chromatin structure, gene expression and cellular development.
- Xiuxiao Tang
- , Pengguihang Zeng
- & Junjun Ding
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