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| Open AccessTDP1 suppresses chromosomal translocations and cell death induced by abortive TOP1 activity during gene transcription
Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs single strand breaks (SSBs) generated by DNA topoisomerase I (TOP1). Here the authors show that TDP1 also repairs TOP1-induced double strand breaks (DSBs).
- Diana Rubio-Contreras
- & Fernando Gómez-Herreros
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Article
| Open AccessRational design of microRNA-responsive switch for programmable translational control in mammalian cells
Artificial regulation of translation by intracellular RNAs has many potential applications. Here, authors design a platform capable of miRNA-triggered upregulation or downregulation using a single RNA construct, and demonstrate its use in constructing logic gates and cell-type classifiers.
- Hui Ning
- , Gan Liu
- & Zhen Xie
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Article
| Open AccessSpatial transcriptomics uncover sucrose post-phloem transport during maize kernel development
Maize kernels have long intrigued researchers due to their complex structure. Through microscopic sectioning and spatial transcriptomics, the authors observed the spatial distribution of RNA through electronic RNA in situ hybridization maps and discovered how storage accumulation occurs.
- Yuxin Fu
- , Wenxin Xiao
- & Wenqin Wang
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Article
| Open AccessThemis2 regulates natural killer cell memory function and formation
Innate immunity represents the first line of defence against pathogens, but certain innate cells are capable of memory formation, albeit with different and lesser-known mechanisms than adoptive immune cells. Here authors show that Themis2 regulates both memory NK cell development and function, via distinct downstream pathways.
- Tsukasa Nabekura
- , Elfira Amalia Deborah
- & Akira Shibuya
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Article
| Open AccessTranscriptional reprogramming by mutated IRF4 in lymphoma
Cancer is often associated with mutant transcription factors (TFs) but their functional characterization is challenging. Here, the authors describe a recurrent mutation within TF IRF4 in human lymphomas and they show how it causes a complex switch in TF specificity and functionality.
- Nikolai Schleussner
- , Pierre Cauchy
- & Stephan Mathas
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Article
| Open AccessMePMe-seq: antibody-free simultaneous m6A and m5C mapping in mRNA by metabolic propargyl labeling and sequencing
Methylation is the dominant modification in mRNA and occurs at a variety of sites. Here, Hartstock et al. show that a clickable analogue of the key cosubstrate S-adenosyl-L-methionine (SAM) can be produced in cells, allowing for identification and mapping of different methylated nucleosides in mRNA.
- Katja Hartstock
- , Nadine A. Kueck
- & Andrea Rentmeister
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Article
| Open AccessFunctional dissection of PRC1 subunits RYBP and YAF2 during neural differentiation of embryonic stem cells
RYBP and YAF2 are a pair of paralog subunits of variant PRC1. Here, authors show that RYBP decrease but YAF2 increase during mESC neural differentiation, and that they are not redundant but function differentially in regulating this differentiation.
- Yanjiang Liu
- , Gongcheng Hu
- & Hongjie Yao
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Article
| Open AccessAlternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs
ALT cells use an alternative lengthening mechanism of telomeres and bear telomeric DNA damage with increased levels of damage-induced long non-coding RNA. Here the AUs show that antisense oligonucleotides (ASO) targeting such RNAs can induce ALT cancer cells selective cell death.
- Ilaria Rosso
- , Corey Jones-Weinert
- & Fabrizio d’Adda di Fagagna
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Article
| Open AccessStructure and function of the EA1 surface layer of Bacillus anthracis
S-layers form continuous protein lattices on the surface of bacteria. Here, authors use S-layer depolymerizing nanobodies to solve the structure of the EA1 S-layer in the pathogen Bacillus anthracis and show its role as cell wall supportive structure”
- Adrià Sogues
- , Antonella Fioravanti
- & Han Remaut
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Article
| Open AccessSpliceosome component Usp39 contributes to hepatic lipid homeostasis through the regulation of autophagy
Non-alcoholic fatty liver disease affects 25% of people worldwide. Here the authors report that spliceosome component Usp39 deletion in mice leads to spontaneous steatosis and impaired autophagy through the regulation of alternative splicing.
- Donghai Cui
- , Zixiang Wang
- & Zhaojian Liu
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Article
| Open AccessDissecting the human leptomeninges at single-cell resolution
The meninges protect the central nervous system at the brain border, and its dysfunction can lead to neural inflammation and cell damage. Here, the authors uncover the gene signatures of diverse cell types in the aged human leptomeninges and highlight their changes in Alzheimer’s Disease.
- Nicola A. Kearns
- , Artemis Iatrou
- & Yanling Wang
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Article
| Open AccessStructural basis for stabilisation of the RAD51 nucleoprotein filament by BRCA2
Here the authors report the cryoEM structure of the RAD51 nucleoprotein filament bound to the C-terminal TR2 domain of BRCA2. The structure explains how BRCA2 stabilises the filament and uncovers a conserved mechanism of filament binding by recombination mediators.
- Robert Appleby
- , Luay Joudeh
- & Luca Pellegrini
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Article
| Open AccessThe lncRNA Sweetheart regulates compensatory cardiac hypertrophy after myocardial injury in murine males
LncRNAs take part in fine-tuning gene regulatory networks in development, homeostasis, and disease settings. Here, the authors show that the lncRNA Sweetheart has an important role in cardiomyocytes after myocardial injury to act together with NKX2-5 in adapting gene programs after myocardial stress.
- Sandra Rogala
- , Tamer Ali
- & Phillip Grote
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Article
| Open AccessDouble-strand breaks induce inverted duplication chromosome rearrangements by a DNA polymerase δ-dependent mechanism
Inverted duplications are a type of chromosome rearrangement observed in cancers. Here the authors show that a DNA double-strand break induces high frequency inverted duplications in cells lacking Mre11 nuclease by DNA polymerase δ-dependent mechanism.
- Amr M. Al-Zain
- , Mattie R. Nester
- & Lorraine S. Symington
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Article
| Open AccessGli1 marks a sentinel muscle stem cell population for muscle regeneration
Adult skeletal muscle regeneration is mainly driven by muscle stem cells (MuSCs), which are highly heterogeneous. Here, the authors found that a population of MuSCs, marked by Gli1 expression, is key contributor to muscle regeneration.
- Jiayin Peng
- , Lili Han
- & Yun Zhao
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Article
| Open AccessThe structure of a hibernating ribosome in a Lyme disease pathogen
Ribosomes are prime targets for antibiotics in pathogenic bacteria. Here, cryo-electron microscopy reveals features in the Borrelia burgdorferi ribosome that provide insights into ribosome evolution, dormancy, and antibiotic binding.
- Manjuli R. Sharma
- , Swati R. Manjari
- & Nilesh K. Banavali
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Article
| Open AccessRemodeling the cellular stress response for enhanced genetic code expansion in mammalian cells
Genetic code expansion (GCE) is a protein engineering tool that enables programmed and site-specific installation of noncanonical amino acids into proteins. Here, authors show that cellular stress remodelling boosts GCE in mammalian cells including GCE realized by orthogonally translating organelles.
- Mikhail E. Sushkin
- , Christine Koehler
- & Edward A. Lemke
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Article
| Open AccessHomodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation
CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia progress. Here the authors show that homodimer-mediated phosphorylation of C/EBPα-p42 modulates acute myeloid leukaemia cell differentiation by liquid-liquid phase separation.
- Dongmei Wang
- , Tao Sun
- & Chunyan Ji
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Article
| Open AccessA circular RNA activated by TGFβ promotes tumor metastasis through enhancing IGF2BP3-mediated PDPN mRNA stability
TGFbeta is known to promote cancer metastasis through the promotion of epithelial-mesenchymal transition (EMT). Here, the authors demonstrate that a TGFbeta induced circular RNA (circITGB6) promotes colorectal cancer metastasis via activation of the m6A reader protein, IGF2BP3, resulting in stabilization of an EMT-promoting gene, PDPN.
- Ke Li
- , Jiawei Guo
- & Yong Peng
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Article
| Open AccessN-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity
The most common protein modification in eukaryotes is N-terminal acetylation, but its functional impact has remained enigmatic. Here, the authors find that a key role for N-terminal acetylation is shielding proteins from ubiquitin ligase-mediated degradation, mediating motility and longevity.
- Sylvia Varland
- , Rui Duarte Silva
- & Thomas Arnesen
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Article
| Open AccessChromatinization modulates topoisomerase II processivity
Here the authors discover that chromatin stimulates topoisomerase II function by enabling the enzyme to achieve exceptionally high processivity and efficient supercoiling relaxation, even under low torsional stress.
- Jaeyoon Lee
- , Meiling Wu
- & Michelle D. Wang
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Article
| Open AccessFIGNL1 AAA+ ATPase remodels RAD51 and DMC1 filaments in pre-meiotic DNA replication and meiotic recombination
Assembly and disassembly of RAD51/DMC1 during homologous recombination are tightly regulated. Here, the authors show that the FIGNL1 ATPase limits non-productive assembly of RAD51/DMC1 on single-stranded and double-stranded DNAs during meiosis.
- Masaru Ito
- , Asako Furukohri
- & Akira Shinohara
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Article
| Open AccessRNA-based translation activators for targeted gene upregulation
Many diseases are driven by the insufficient expression of critical genes, but few technologies are capable of rescuing these endogenous protein levels. Here, Cao et al. present an RNA-based technology that boosts protein production from endogenous mRNAs by upregulating their translation.
- Yang Cao
- , Huachun Liu
- & Bryan C. Dickinson
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Article
| Open AccessPAPγ associates with PAXT nuclear exosome to control the abundance of PROMPT ncRNAs
Pervasive transcription of the human genome generates an abundance of RNAs that must be processed and degraded by the nuclear RNA exosome. Here the authors show that polyA polymerase gamma (PAPγ) associates with PAXT providing key insights into the direct targeting of PROMPT ncRNAs by PAXT at their genomic sites.
- Xavier Contreras
- , David Depierre
- & Rosemary Kiernan
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Article
| Open AccessProfiling of the Helicobacter pylori redox switch HP1021 regulon using a multi-omics approach
Helicobacter pylori adapted to the harsh conditions of the human stomach using a handful of regulatory proteins. Here, the authors identify H. pylori processes controlled by the HP1021 response regulator under optimal growth and oxidative stress.
- Mateusz Noszka
- , Agnieszka Strzałka
- & Anna Zawilak-Pawlik
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Article
| Open AccessMetabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction
How cellular metabolism is connected to differentiation remains poorly understood. Here the authors report a regulatory cascade in which circulating citrate regulates sperm production by controlling protein stability via a specific protein post-translational modification.
- Charlotte M. François
- , Thomas Pihl
- & Bruno Hudry
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Article
| Open AccessUV-induced G4 DNA structures recruit ZRF1 which prevents UV-induced senescence
Senescence can be activated in a DNA damage-dependent and -independent manner. Here the authors reveal in cell lines that recruitment of the factor ZRF1 at G4 DNA structures can prevents UV-induced senescence.
- Alessio De Magis
- , Michaela Limmer
- & Katrin Paeschke
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Article
| Open AccessTelomouse—a mouse model with human-length telomeres generated by a single amino acid change in RTEL1
Telomeres are the protective caps of the chromosomes, which shorten with age. Smoom and colleagues developed a mouse strain with human-size telomeres. This mouse, termed Telomouse, is therefore an invaluable tool for studying human aging and cancer.
- Riham Smoom
- , Catherine Lee May
- & Yehuda Tzfati
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Article
| Open AccessDNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts
Epigenetic therapies are known to synergize with immunotherapies through the de-repression of endogenous retroviral element (ERV)-encoded promoters. Here the authors identify treatment-induced neoantigens and validate their ability to induce T cell response and anti-tumor effects in vitro and in patient samples.
- Ashish Goyal
- , Jens Bauer
- & Christoph Plass
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Article
| Open AccessPhase separation of BuGZ regulates gut regeneration and aging through interaction with m6A regulators
Phase separation serves to compartmentalize and concentrate cellular components to facilitate essential physiological processes. Here, the authors elucidate the role and mechanism of BuGZ-mediated phase separation in the context of gut regeneration and aging.
- Qiaoqiao Zhang
- , Kai Deng
- & Hao Jiang
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Article
| Open AccessStructure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir
The HIV-1 entry inhibitor temsavir prevents the interaction of the envelope glycoprotein with its cellular receptor. Here, authors apply CryoEM to show that HIV-1 clade AE resistance to temsavir is a combination of the residue at position 375 (His) and mutations in the gp120 mobile layers. Mutation of His375 to Ser/Thr and reversion of the layer mutations are required to restore temsavir sensitivity.
- Jérémie Prévost
- , Yaozong Chen
- & Marzena Pazgier
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Article
| Open AccessA chromatinized origin reduces the mobility of ORC and MCM through interactions and spatial constraint
Here the authors investigate the impact of chromatinizing origins of replication on ORC and MCM is at the single-molecule level. They find mobility of ORC reduced, but not its binding to the origin. MCM is both efficiently recruited and spatially confined to the origin.
- Humberto Sánchez
- , Zhaowei Liu
- & Nynke H. Dekker
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Article
| Open AccessmRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy
Large genes require dual adeno-associated viral (AAV) vectors for in vivo delivery/expression, but current methods have limitations. Here the authors develop and functionally evaluate REVeRT, an efficient and flexible dual AAV vector technology based on reconstitution via mRNA trans-splicing.
- Lisa Maria Riedmayr
- , Klara Sonnie Hinrichsmeyer
- & Elvir Becirovic
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Article
| Open AccessPaired yeast one-hybrid assays to detect DNA-binding cooperativity and antagonism across transcription factors
Combinations of transcription factors (TFs) bind DNA to fine-tune gene expression. Here, the authors map cooperative and antagonistic DNA binding across hundreds of TF-pairs. TF-TF relationships vary depending on DNA targets and TF isoforms.
- Anna Berenson
- , Ryan Lane
- & Juan I. Fuxman Bass
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Article
| Open AccessConserved enhancers control notochord expression of vertebrate Brachyury
This study identifies three conserved shadow enhancers (T3, C, I) regulating notochord expression of Brachyury across vertebrates using genomic data, transgenic assays, and enhancer knockouts, which are critical for vertebrate notochord development.
- Cassie L. Kemmler
- , Jana Smolikova
- & Alexa Burger
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Article
| Open AccessThe SMN complex drives structural changes in human snRNAs to enable snRNP assembly
Sm protein binding to pre-snRNA is a key step in snRNP biogenesis catalyzed by the SMN complex. Here, the authors show that pre-snRNAs adopt compact structures incompatible with Sm protein binding and that Gemin3 and 4 are required for pre-snRNA rearrangement to allow Sm protein interaction.
- Josef Pánek
- , Adriana Roithová
- & David Staněk
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Article
| Open AccessPhagocytosis-initiated tumor hybrid cells acquire a c-Myc-mediated quasi-polarization state for immunoevasion and distant dissemination
The CD47/SIRPα axis is well known to mediate immune escape by promoting cancer resistance to phagocytosis. Here the authors show that low CD47-expressing prostate cancer cells still allow phagocytosis but the process is incomplete leading to the formation of macrophage:tumor hybrid cells with immune evasive and pro-metastatic properties.
- Chih-Wei Chou
- , Chia-Nung Hung
- & Tim Hui-Ming Huang
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Article
| Open AccessALKBH5 controls the meiosis-coupled mRNA clearance in oocytes by removing the N 6-methyladenosine methylation
N6-methyladenosine (m6A) maintains maternal RNA stability in oocytes. Here, the authors identify demethylase ALKBH5 as a key determinant of oocyte quality and unveil the facilitating role of ALKBH5-mediated m6A removal in maternal RNA decay.
- Long Bai
- , Yu Xiang
- & Yimin Zhu
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Article
| Open AccessFibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis
Fibrocystin/Polyductin (FPC) is a large ciliary membrane protein encoded by PKHD1 which, when mutated, causes ARPKD. Here, the authors show that FPC suppresses cyst development in the kidney of mouse models through the release and mitochondrial translocation of its C terminal product.
- Rebecca V Walker
- , Qin Yao
- & Feng Qian
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Article
| Open AccessGenome-wide analysis of the interplay between chromatin-associated RNA and 3D genome organization in human cells
How chromatin-associated RNAs (caRNAs) are spatially organized in the context of the multiscale genome architecture is unclear. Here the authors suggest how the 3D genome architecture can modulate the spatial distribution of caRNAs at different scales, and how in turn caRNA could affect the dynamic 3D genome organization.
- Riccardo Calandrelli
- , Xingzhao Wen
- & Sheng Zhong
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Article
| Open AccessChromatin organization drives the search mechanism of nuclear factors
Nuclear factors rapidly scan the genome for targets, but the role of nuclear organization in such search is uncharted. Here, by combining single molecule tracking of nuclear proteins with high resolution imaging of the nucleus, the authors investigate the search mechanism used by factors such as p53.
- Matteo Mazzocca
- , Alessia Loffreda
- & Davide Mazza
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Article
| Open AccessStructure of the transcription open complex of distinct σI factors
Here the authors show that σI factors encompass a unique, hitherto-unknown recognition mode of bacterial transcriptional promoters and represent a new distinctive class of σ70-family σ factors for bacterial transcription.
- Jie Li
- , Haonan Zhang
- & Ping Zhu
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Article
| Open AccessDigital data storage on DNA tape using CRISPR base editors
DNA is an alternative to data storage materials for its durability, density, and energetics. Here the authors demonstrate the storage of digital information on DNA molecules using base-editing.
- Afsaneh Sadremomtaz
- , Robert F. Glass
- & Reza Zadegan
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Article
| Open AccessSpecies-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction
The innate immune cells undergo metabolic reprogramming upon inflammation. Here, the authors report that both mouse and human microglia display a metabolic reprogramming in the presence of a TLR4 activation, however species-specific enzymes are responsible for this process.
- Angélica María Sabogal-Guáqueta
- , Alejandro Marmolejo-Garza
- & Amalia Dolga
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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
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Article
| Open AccessTranscriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription
Aberrant hypertranscription in cells can affect development and disease. Here, the authors show that DNA topoisomerase I prevents hypertranscription; not through its catalytic function, but through a DNA binding mechanism.
- Mei Sheng Lau
- , Zhenhua Hu
- & Wee-Wei Tee
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Article
| Open AccessMYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM)
Arrhythmogenic cardiomyopathy is an untreatable heart muscle disease and a common cause of sudden cardiac death in young athletes. The authors show a link between actomyosin dysregulation and cardiac dysfunction by studying nonsense PKP2 mutants classified as pathogenic to identify a potential treatment.
- Nieves García-Quintáns
- , Silvia Sacristán
- & Juan A. Bernal
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Article
| Open AccessHMGA2 directly mediates chromatin condensation in association with neuronal fate regulation
High-mobility group AT-hook (HMGA) proteins 1 and 2 are nonhistone chromatin proteins involved in different biological processes. Here the authors reveal that HMGA2 is a bona fide chromatin condensation factor that undergoes liquid–liquid phase separation, and that its chromatin condensation activity is important for the maintenance of mouse neural progenitor cells.
- Naohiro Kuwayama
- , Tomoya Kujirai
- & Yukiko Gotoh
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Article
| Open AccessUnaltered hepatic wound healing response in male rats with ancestral liver injury
How much the environment influences inherited adaptive traits is debated and challenging to demonstrate in mammals. Here the authors performed a multigeneration study that failed to morphologically replicate enhanced wound healing response following ancestral liver injury in rats. However, heritable transcriptional effects suggest transmission at the molecular level, albeit of unclear functional relevance.
- Johanna Beil
- , Juliane Perner
- & Rémi Terranova
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