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| Open AccessANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation
The transcriptional program controlling the activation of cancer-associated fibroblasts (CAFs) remains to be elucidated. Here, the authors identify ANKRD1 as a mesenchymal-specific driver of CAF activation under negative direct control of androgen receptor, triggering AP-1 transcription factor complex activation.
- Luigi Mazzeo
- , Soumitra Ghosh
- & G. Paolo Dotto
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Article
| Open AccessThe chromatin-associated lncREST ensures effective replication stress response by promoting the assembly of fork signaling factors
Replication stress represents a major threat to genome integrity of normal and cancer cells. Here, the authors find that the long non-coding RNA lncREST affects the replication stress response through interaction with nucleolin. This interaction bridges the recruitment of replication factors to stressed chromatin.
- Luisa Statello
- , José Miguel Fernandez-Justel
- & Maite Huarte
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Article
| Open AccessTissue-specific profiling of age-dependent miRNAomic changes in Caenorhabditis elegans
Wang et al. profile age-dependent miRNAomic changes in worm tissues and extracellular vesicles (EVs). They show that ageing controls miRNAs in a tissue-specific manner and their findings further suggest a complex EV-mediated miRNA trafficking network across tissues.
- Xueqing Wang
- , Quanlong Jiang
- & Yidong Shen
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Article
| Open AccessRan-GTP assembles a specialized spindle structure for accurate chromosome segregation in medaka early embryos
Mitotic spindle assembles in each blastomere to segregate duplicated chromosomes during cleavage of the fertilized egg. Here, the authors establish functional assays in fish embryos and find that Ran-GTP assembles a microtubule network at the metaphase spindle center that is essential for chromosome segregation.
- Ai Kiyomitsu
- , Toshiya Nishimura
- & Tomomi Kiyomitsu
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Article
| Open AccessAnti-CRISPR Anopheles mosquitoes inhibit gene drive spread under challenging behavioural conditions in large cages
CRISPR-based gene drives have the potential to spread within populations and are considered as promising vector control tools. Here the authors show an anti-drive mosquito strain that prevents the spread and collapse of a population suppression gene drive in laboratory Anopheles mosquito large cage trials in complex ecological and behavioral conditions.
- Rocco D’Amato
- , Chrysanthi Taxiarchi
- & Ruth Müller
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Article
| Open AccessHRDE-2 drives small RNA specificity for the nuclear Argonaute protein HRDE-1
Argonaute proteins are loaded with small RNAs to confer target RNA specificity and proper gene silencing. Here, the authors establish that HRDE-2 recruits the unloaded nuclear Argonaute HRDE-1 to germ granules to facilitate correct small RNA loading.
- Shihui Chen
- & Carolyn M. Phillips
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Article
| Open AccessMultiplexed screening reveals how cancer-specific alternative polyadenylation shapes tumor growth in vivo
Dysregulation of alternative polyadenylation (APA) is associated with poor prognosis in cancer but its functional role is less clear. Here, the authors develop a CRISPR-Cas9- based screen to determine the effects of different APA events on melanoma growth in mouse models.
- Austin M. Gabel
- , Andrea E. Belleville
- & Robert K. Bradley
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Article
| Open AccessUbiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates
Upon cold exposure, two types of thermogenic fat cells, brown and beige adipocytes, are sequentially activated. Here, the authors show that E3 ubiquitin ligase RNF20 coordinates the sequential thermogenic activation through fat depot specific substrates.
- Yong Geun Jeon
- , Hahn Nahmgoong
- & Jae Bum Kim
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Article
| Open AccessFLIP(C1orf112)-FIGNL1 complex regulates RAD51 chromatin association to promote viability after replication stress
Recombination is essential for life. Here, the authors characterize FLIP as a novel regulator of the key recombination protein RAD51’s functions. FLIP loss caused marked sensitivity to DNA damage, increased DNA breakage and defective replication.
- Jessica D. Tischler
- , Hiroshi Tsuchida
- & Richard O. Adeyemi
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Article
| Open AccessExpanded palette of RNA base editors for comprehensive RBP-RNA interactome studies
RNA base-editors are often used in methods for RNA binding protein (RBP) target discovery. Here the authors present a new RBP target discovery method, PRINTER, and suggest optimal RNA base-editors for dual-RBP studies, emphasizing the importance of matching rBEs’ editing biases with RBPs’ binding preferences.
- Hugo C. Medina-Munoz
- , Eric Kofman
- & Gene W. Yeo
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Article
| Open AccessRNA polymerase II pausing is essential during spermatogenesis for appropriate gene expression and completion of meiosis
Gene expression dynamics are tightly regulated during spermatogenesis, with disruptions resulting in infertility. Here they identify a critical role for RNA PolII pausing in spermatogenesis and show that loss of the RNA PolII pausing factor NELF causes meiotic arrest.
- Emily G. Kaye
- , Kavyashree Basavaraju
- & Prabhakara P. Reddi
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Article
| Open AccessSemi-supervised integration of single-cell transcriptomics data
Batch effects hinder multi-sample single-cell data analyses. Here, authors present STACAS, a scalable single-cell RNA-seq data integration tool that uses prior cell type knowledge to preserve biological variability, demonstrating robustness to noisy input cell type labels.
- Massimo Andreatta
- , Léonard Hérault
- & Santiago J. Carmona
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Article
| Open AccessEngineering a transposon-associated TnpB-ωRNA system for efficient gene editing and phenotypic correction of a tyrosinaemia mouse model
Miniature gene editing tools are highly desired for efficient in vivo delivery and disease treatment. Here, the authors reported engineering hypercompact TnpB-ωRNA for robust gene editing with minimal off-target effect in cultured cells and use it to rescue fatal genetic liver disease in a tyrosinaemia mouse model.
- Zhifang Li
- , Ruochen Guo
- & Chunlong Xu
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Article
| Open AccessCaloric restriction leads to druggable LSD1-dependent cancer stem cells expansion
Caloric restriction (CR) has been demonstrated to have a role in tumour growth and therapy response but its effects on cancer stem cells are less known. Here, in Acute Promyelocytic Leukemia, the authors show that despite initial anti-tumour effect, CR drives the selection of leukaemia-initiating cells resulting in relapse which could be prevented by ablation of LSD1.
- Rani Pallavi
- , Elena Gatti
- & Pier Giuseppe Pelicci
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Article
| Open AccessTrajectory inference across multiple conditions with condiments
scRNA-Seq has enabled the study of dynamic systems such as response to a drug at the individual cell and gene levels. Here the authors introduce a framework to interpret differences at the trajectory, cell populations, and individual gene levels.
- Hector Roux de Bézieux
- , Koen Van den Berge
- & Sandrine Dudoit
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Article
| Open AccessUsing deep learning to quantify neuronal activation from single-cell and spatial transcriptomic data
Neuronal activity is associated with transcriptional changes. Here, the authors present a deep learning model that integrates single cell transcriptomic signals to estimate neuronal activation.
- Ethan Bahl
- , Snehajyoti Chatterjee
- & Jacob J. Michaelson
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Article
| Open Access2.7 Å cryo-EM structure of human telomerase H/ACA ribonucleoprotein
Here the authors captured the structure of human telomerase H/ACA ribonucleoprotein (RNP) by cryo-EM. The structure rationalizes telomere-disorder disease mutations and reveals insights into the mechanism of pseudouridylation by eukaryotic H/ACA RNPs.
- George E. Ghanim
- , Zala Sekne
- & Thi Hoang Duong Nguyen
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Article
| Open AccessAKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis
The metabolic switch of tumours to aerobic glycolysis can allow them to meet their increasing energetic demands. Here, the authors show that AKT1 regulates this switch through the phosphorylation of malic enzyme 2 (ME2) preventing mitochondrial translocation. In turn this pushes the cell from mitochondrial metabolism to glycolysis, promoting tumour growth.
- Taiqi Chen
- , Siyi Xie
- & Wenjing Du
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Article
| Open AccessLOX-1 acts as an N6-methyladenosine-regulated receptor for Helicobacter pylori by binding to the bacterial catalase
N6-methyladenosine (m6A) modification of mRNA regulates gene expression in eukaryotes. Here, Zeng et al. show that m6A modification of mRNAs contributes to protection against the pathogen Helicobacter pylori by downregulating a host protein that acts as receptor for the pathogen.
- Judeng Zeng
- , Chuan Xie
- & William K. K. Wu
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Article
| Open AccessCryo- EM structure of the mycobacterial 70S ribosome in complex with ribosome hibernation promotion factor RafH
Ribosome hibernation is a key survival strategy bacteria adapt under stress. Here, cryo- EM structure of mycobacterial 70S ribosome with hypoxia stress-induced factor RafH suggests the molecular mechanism of RafH-induced ribosome hibernation.
- Niraj Kumar
- , Shivani Sharma
- & Prem S. Kaushal
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Article
| Open AccessThe CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells
CD8 + T cells are central players in anti-tumour immunity. Here authors identify Cul5, a ubiquitin E3 ligase as an important inhibitor of CD8 + T cell anti-tumour cytotoxicity and persistence via involvement with both T cell receptor and cytokine-regulated central pathways.
- Xiaofeng Liao
- , Wenxue Li
- & Dianqing Wu
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Article
| Open AccessDeath Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer’s disease and aging
Events that cause neurons to die in Alzheimer’s disease (AD) are poorly understood. Here, the authors provide evidence for a role of RNA interference in AD. Short RNAs causing neurotoxicity and DNA damage are seen in AD and aged brains, and are counteracted by nontoxic RNAs.
- Bidur Paudel
- , Si-Yeon Jeong
- & Marcus E. Peter
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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
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Article
| Open AccessStructural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy
In this work, the authors report Cryo-EM imaging revealing diversity in amyloid fibril structures among ATTR patients with the same genetic mutation I84S. Further study is warranted to grasp the implications in ATTR amyloidosis pathology.
- Binh An Nguyen
- , Virender Singh
- & Lorena Saelices
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Article
| Open AccessAntibody-dependent enhancement of toxicity of myotoxin II from Bothrops asper
The recent emergence of monoclonal antibodies able to neutralize snake toxins have revolutionized the approach of developing novel therapies to treat snakebite envenoming, at least in animal models. Here, the authors show antibody-dependent enhancement of toxicity (ADET) for a toxin derived from snake venom and highlight the importance of this phenomenon when testing therapeutic antibodies against snake venoms in animal models.
- Christoffer V. Sørensen
- , Julián Fernández
- & Andreas H. Laustsen
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Article
| Open AccessStructural differences between the closely related RNA helicases, UAP56 and URH49, fashion distinct functional apo-complexes
UAP56 is an important factor in the TREX complex, which is responsible for mRNA export. Here the authors show that the closely related RNA helicases, UAP56 and URH49, exhibit different three-dimensional structures due to one amino acid change. Accordingly, they form distinct apo-complexes and function in the nuclear export of specific target mRNAs.
- Ken-ichi Fujita
- , Misa Ito
- & Seiji Masuda
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Article
| Open AccessStructural basis of antiphage immunity generated by a prokaryotic Argonaute-associated SPARSA system
Short prokaryotic Argonaute and Sir2 proteins function as an antivirus system. Here the authors describe structures of SPARSA (a heterodimer of Sir2-APAZ and prokaryotic Argonaute) with and without template DNA and guide RNA, providing structural basis of its assembly and activation by the recognition of the invading virus.
- Xiangkai Zhen
- , Xiaolong Xu
- & Songying Ouyang
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Article
| Open AccessThe chromatin landscape of healthy and injured cell types in the human kidney
Comprehensive integration of gene expression with epigenetic features is needed to understand the transition of kidney cells from health to injury. Here, the authors integrate dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and histone modifications to decipher the chromatin landscape of the kidney in reference and adaptive injury cell states, identifying a transcription factor network of ELF3, KLF6, and KLF10 which regulates adaptive repair and maladaptive failed repair.
- Debora L. Gisch
- , Michelle Brennan
- & Michael T. Eadon
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Article
| Open AccessOvercoming resolution attenuation during tilted cryo-EM data collection
Here, the authors quantify the effect of cryo-EM data acquisition with stage-tilt on the global resolution of reconstructions and present a tool for predicting an optimal stage-tilt angle to ameliorate the effects of preferred specimen orientation.
- Sriram Aiyer
- , Philip R. Baldwin
- & Dmitry Lyumkis
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Article
| Open AccessA full-body transcription factor expression atlas with completely resolved cell identities in C. elegans
Invariant cell lineage in C. elegans enables the analysis of transcriptional regulatory mechanisms controlling the fate of each cell at spatiotemporal resolution. Here, the authors develop a tool automating C. elegans cell identification and create an expression atlas of 620 transcription factors.
- Yongbin Li
- , Siyu Chen
- & Xiao Liu
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Article
| Open AccessPSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity
R-loop accumulation at transcription sites poses a persistent threat to genome integrity. Here the authors demonstrate a role for PSIP1/LEDGF protein in reducing R-loop levels at the site of transcription and preventing transcription replication conflict to maintain genome integrity.
- Sundarraj Jayakumar
- , Manthan Patel
- & Madapura M. Pradeepa
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Article
| Open AccesshnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS)
HnRNP A1 dysfunction is associated with neurodegeneration in multiple sclerosis (MS). Herein, advanced RNA sequencing and CLIPseq of MS brains and relevant models demonstrated that hnRNP A1 binding of target RNAs and RNA splicing were altered, precipitating neurodegeneration.
- Hannah E. Salapa
- , Patricia A. Thibault
- & Michael C. Levin
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Article
| Open AccessSilica-associated proteins from hexactinellid sponges support an alternative evolutionary scenario for biomineralization in Porifera
Sponges, being early-diverging metazoans and the only animals to develop extensive skeletons of silica, have potential to inform about the evolutionary steps of metazoan traits, including biomineralization. Here, the authors characterize two proteins associated with the hexactinellid sponge silica.
- Katsuhiko Shimizu
- , Michika Nishi
- & Manuel Maldonado
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Article
| Open AccessNuclear Hsp104 safeguards the dormant translation machinery during quiescence
During aging, proteins are damaged and can misfold, compromising cellular viability. Here, Kohler et al. uncover how aging cells maintain fitness by redirecting the protein repair factor Hsp104 to the nucleus in response to metabolic cues.
- Verena Kohler
- , Andreas Kohler
- & Sabrina Büttner
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Article
| Open AccessTail-tape-fused virion and non-virion RNA polymerases of a thermophilic virus with an extremely long tail
The authors describe the structure and function of two evolutionarily diverged RNA polymerases of a thermophilic phage. One of the polymerases is fused to the phage tape measure protein, a virion component dictating the length of the phage tail.
- Anastasiia Chaban
- , Leonid Minakhin
- & Maria L. Sokolova
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Article
| Open AccessThe virulence regulator VirB from Shigella flexneri uses a CTP-dependent switch mechanism to activate gene expression
Protein VirB regulates the expression of virulence genes in the pathogen Shigella flexneri by binding to DNA sequences far upstream of their promoters. Here, Jakob et al. show that VirB acts as a CTP-dependent molecular switch that uses a loading-and-sliding mechanism to control transcription of its target genes.
- Sara Jakob
- , Wieland Steinchen
- & Martin Thanbichler
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Article
| Open AccessThe single-cell transcriptomic atlas and RORA-mediated 3D epigenomic remodeling in driving corneal epithelial differentiation
Ocular homeostasis and vision depend on the differentiation of limbal stem/progenitor cells into corneal epithelial cells. Here, the authors report transcriptional dynamics and RORA-mediated epigenetic remodeling underlying the differentiation of human corneal epithelium.
- Mingsen Li
- , Huizhen Guo
- & Hong Ouyang
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Article
| Open AccessSystems-based identification of the Hippo pathway for promoting fibrotic mesenchymal differentiation in systemic sclerosis
Systemic sclerosis (SSc) is an autoimmune disease causing skin fibrosis and organ inflammation. Here the authors generate and analyze SSc skin single cell RNA sequencing data to propose contributions from both myofibroblasts and endothelial-to-mesenchymal -transitioning cells (EndoMT) to skin fibrosis, and to implicate the involvement of Hippo signaling pathways.
- Feiyang Ma
- , Pei-Suen Tsou
- & Johann E. Gudjonsson
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Article
| Open AccessHistone lactylation couples cellular metabolism with developmental gene regulatory networks
While metabolic reprogramming has been shown to drive changes in cell identity, the link between cellular metabolism and gene expression remains poorly characterized. Here they show that histone lactylation couples metabolism and transcription during neural crest cell differentiation in the early embryo.
- Fjodor Merkuri
- , Megan Rothstein
- & Marcos Simoes-Costa
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Article
| Open AccessMapping nucleosome-resolution chromatin organization and enhancer-promoter loops in plants using Micro-C-XL
The authors employ Micro-C-XL to investigate chromatin structures in plants, specifically focusing on nucleosome-resolution chromatin organizations and enhancer-promoter chromatin loops in Arabidopsis, rice, and soybean.
- Linhua Sun
- , Jingru Zhou
- & Hang He
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Article
| Open AccessMutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response
Here the authors show that gain-of-function mutant p53s predispose cells to chromosomal instability by targeting MCMs, leading to activation of a cGAS-STING-non-canonical NF-κB signaling that promotes tumor metastasis and immunosuppression.
- Mei Zhao
- , Tianxiao Wang
- & Ge Zhou
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Article
| Open AccessAspergillus fumigatus mitogen-activated protein kinase MpkA is involved in gliotoxin production and self-protection
Aspergillus fumigatus produces the mycotoxin gliotoxin which is important for virulence. Here, de Castro et al characterise how excess production and subsequent fungal toxicity is controlled by the mitogen-activated protein kinase MpkA.
- Patrícia Alves de Castro
- , Camila Figueiredo Pinzan
- & Gustavo H. Goldman
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Article
| Open AccessQuantifying negative selection in human 3ʹ UTRs uncovers constrained targets of RNA-binding proteins
Identifying functional genetic variants in non-coding regions of the human genome is challenging. Here the authors apply their iMAPS approach to 3ʹ untranslated regions, identifying thousands of variants that disrupt post-transcriptional gene regulation.
- Scott D. Findlay
- , Lindsay Romo
- & Christopher B. Burge
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Article
| Open AccessRole of UPF1-LIN28A interaction during early differentiation of pluripotent stem cells
UPF1 and LIN28A are RNA-binding proteins involved in post-transcriptional regulation and cell differentiation. Here, authors report that they interact with each other via specific domains and regulate ectodermal specialization of human pluripotent stem cells.
- Seungwon Jung
- , Seung Hwan Ko
- & Jungwook Hwang
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Article
| Open AccessPrimase promotes the competition between transcription and replication on the same template strand resulting in DNA damage
Resolving R-loops caused by transcription-replication conflicts (TRCs) is vital to genome stability in organisms. Here, the authors show that the chloroplast-localized primase ATH intensifies template strand competition and exacerbates the Head-On TRCs induced DNA damage.
- Weifeng Zhang
- , Zhuo Yang
- & Qianwen Sun
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Article
| Open AccessStabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells
Post-translational modifications including protein sumoylation is under specific regulation in glioma stem cells (GSCs). Here, the authors show that Pin1 is deubiquitinated and stabilized by USP34, which in turn promotes isomerization of Ubc9, leading to SUMO1-modified global hypersumoylation to maintain the tumorigenic capacity of GSCs.
- Qiuhong Zhu
- , Panpan Liang
- & Wenchao Zhou
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Article
| Open AccessCell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions
Here, the authors show how the histone methyltransferase SETDB1 is involved in cell-type specific regulation of chromatin landscape by catalyzing H3K9me3, which antagonizes CTCF binding. They further define the subsequent transcriptomic impact.
- Phoebe Lut Fei Tam
- , Ming Fung Cheung
- & Danny Leung
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Article
| Open AccessStructural basis for DNA proofreading
Here, the authors use cryo-EM to capture nine intermediates along the DNA proofreading pathway using human mitochondrial DNA Polymerase Gamma. The results provide a step-by-step view of the DNA proofreading at single-nucleotide resolution.
- Gina Buchel
- , Ashok R. Nayak
- & Dmitry Temiakov
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Article
| Open AccessUnraveling the causal genes and transcriptomic determinants of human telomere length
Variation in human telomere length has been well studied, but most previous studies have used adult telomere length. Here, the authors explore the genetic basis of telomere length in the placenta and find suggestive causal genes modulating human telomere length.
- Ying Chang
- , Yao Zhou
- & Dandan Huang
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