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| Open AccessEndothelial deletion of PTBP1 disrupts ventricular chamber development
Alternative splicing crucially affects various biological processes, however, its function in heart development is largely unknown. Here, the authors show an essential role of alternative splicing factor PTBP1 in ventricular chamber development.
- Hongyu Liu
- , Ran Duan
- & Yi-Han Chen
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Article
| Open AccessThe RNA-binding protein hnRNP F is required for the germinal center B cell response
The germinal centre (GC) response is characterized by regulated production of high affinity, class-switched antibodies in response to T-cell dependent antigens. Here authors show that the GC response is not only regulated at the transcriptional and protein levels, but also by the RNA-binding protein hnRNP F via alternative splicing of the co-stimulatory molecule CD40.
- Hengjun Huang
- , Yuxing Li
- & Xijun Ou
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Article
| Open AccessThe m6A reader PRRC2A is essential for meiosis I completion during spermatogenesis
Modification of RNA with m6A has been shown to be important during spermatogenesis. Here they identify post-transcriptional functions of PRRC2A, showing it promotes transcriptome transition from spermatogonia to spermatocytes and the translation of genes related to cell division.
- Xinshui Tan
- , Caihong Zheng
- & Fengchao Wang
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Article
| Open AccessIntegrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer
Analysing the regulatory consequences of mutations and splice variants at large scale in cancer requires efficient computational tools. Here, the authors develop RegTools, a software package that can identify splice-associated variants from large-scale genomics and transcriptomics data with efficiency and flexibility.
- Kelsy C. Cotto
- , Yang-Yang Feng
- & Malachi Griffith
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Article
| Open AccessAdipocyte YTH N(6)-methyladenosine RNA-binding protein 1 protects against obesity by promoting white adipose tissue beiging in male mice
Activation of white adipose tissue (WAT) thermogenesis alleviates obesity-associated metabolic disorders in rodents. Here the authors report that the m6 A RNA modification reader YTHDF1 promotes WAT thermogenesis in a study with male mice, and may be a potential target for the treatment of obesity.
- Sujun Yan
- , Xiaoling Zhou
- & Xiangwei Gao
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Article
| Open AccessThe cellular and KSHV A-to-I RNA editome in primary effusion lymphoma and its role in the viral lifecycle
The Karijolich laboratory describes an atlas of A-to-I RNA editing during the KSHV lifecycle in primary effusion lymphoma. These analyses identified conserved editing events within a viral-encoded microRNA, revealing a critical role for the microRNA and its modification in virus infection.
- Suba Rajendren
- , Xiang Ye
- & John Karijolich
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Article
| Open AccessQuantitative analysis of C. elegans transcripts by Nanopore direct-cDNA sequencing reveals terminal hairpins in non trans-spliced mRNAs
C. elegans long read transcriptomic analysis provides evidence that non-trans-spliced mRNAs display a terminal a hairpin structure mimicking the Spliced Leader. This provides an explanation how the main maturation system might be bypassed.
- Florian Bernard
- , Delphine Dargère
- & Denis Dupuy
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Article
| Open AccessrRNA methylation by Spb1 regulates the GTPase activity of Nog2 during 60S ribosomal subunit assembly
Regulation of 60S biogenesis remains poorly understood. Using cryo-EM, the authors show that failure of Spb1 to methylate the A-loop nucleotide G2922 prematurely activates the GTPase Nog2, suggesting that Spb1 and Nog2 form a kinetic checkpoint during ribosome maturation.
- Kamil Sekulski
- , Victor Emmanuel Cruz
- & Jan P. Erzberger
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Article
| Open AccessInhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment
m6A modification has been reported to play roles in many developmental and pathological processes, but its role in AKI remains poorly understood. Here, the authors show the role and the mechanism of the m6A demethylase, ALKBH5 on IRI induced AKI.
- Juntao Chen
- , Cuidi Xu
- & Tongyu Zhu
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Article
| Open AccessDifferential regulation of mRNA stability modulates transcriptional memory and facilitates environmental adaptation
Transcriptional memory is key for cellular adaptation. Here the authors show that differences in mRNA stability and mRNA degradation machinery between naïve and primed cells facilitate faster gene expression response to repeated stimuli.
- Bingnan Li
- , Patrice Zeis
- & Vicent Pelechano
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Article
| Open AccessNsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis
Th17 cells produce a range of characteristic Th17 type cytokines and express transcription factors governed by epigenetic regulation to engage the Th17 programme. Here the authors implicate the RNA 5- methylcytosine (m5C) methyltransferase Nsun2 in Th17 cells and the promotion of colitis in a murine model.
- Wen-Lan Yang
- , Weinan Qiu
- & Yun-Gui Yang
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Article
| Open AccessAPOBEC3B drives PKR-mediated translation shutdown and protects stress granules in response to viral infection
APOBEC’s are a family of cytidine deaminases that induce mutations in viruses to inhibit their replication and maintain cell integrity. Here, Manjunath et al show that APOBEC3B also inhibits viral replication by stimulating the innate immune sensor protein kinase R causing translational shutdown and stress granule formation independently of its cytidine deaminase activity.
- Lavanya Manjunath
- , Sunwoo Oh
- & Rémi Buisson
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Article
| Open AccessMechanistic insights into RNA surveillance by the canonical poly(A) polymerase Pla1 of the MTREC complex
Here the authors show how the MTREC core protein Red1 binds to and sequesters Pla1 from the 3’-end processing machinery to hyperadenylate cryptic unstable transcripts and target them to the exosome for efficient degradation.
- Komal Soni
- , Anusree Sivadas
- & Tamás Fischer
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Article
| Open AccessSplicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death
Nonalcoholic steatohepatitis (NASH) is an advanced form of fatty liver disease with complex pathogenic mechanisms. Here, the authors report that SRSF1 deficiency in mice livers provokes deleterious R-loop formation and genotoxicity, which impedes hepatocellular gene expression, metabolism, and lipid trafficking, resulting in NASH-like pathology.
- Waqar Arif
- , Bhoomika Mathur
- & Auinash Kalsotra
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Article
| Open AccessTemporal-iCLIP captures co-transcriptional RNA-protein interactions
Dynamic RNA-protein interactions govern the co-transcriptional packaging of RNA polymerase II derived transcripts. Here the authors use temporal-iCLIP which combines transcriptional synchronisation with UV cross-linking of RNA-protein complexes to reveal dynamic RNA-protein interactions during the early phases of transcription and beyond.
- Ross A. Cordiner
- , Yuhui Dou
- & Torben Heick Jensen
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Article
| Open AccessCryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3
The authors report the Cryo-EM of hnRNPDL-2 fibrils. The structure highlights features of a functional amyloid associated with limb-girdle muscular dystrophy-3 and explains how alternative splicing controls the assembly of this ribonucleoprotein.
- Javier Garcia-Pardo
- , Andrea Bartolomé-Nafría
- & Salvador Ventura
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Article
| Open AccessStress promotes RNA G-quadruplex folding in human cells
rG4s are G-quadruplex structures found in transcriptome. Many RNAs can fold into rG4s in vitro, yet their folding and functions in vivo are not well understood. Here the authors showed that rG4s folding is dynamically regulated under stress in human cells.
- Prakash Kharel
- , Marta Fay
- & Pavel Ivanov
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Article
| Open AccessThe interferon stimulated gene-encoded protein HELZ2 inhibits human LINE-1 retrotransposition and LINE-1 RNA-mediated type I interferon induction
Proteomic analyses revealed that a group of interferon-stimulated genes suppresses LINE-1 retrotransposon activities, including HELZ2, which reduces LINE-1 RNA and the associated innate immune response levels.
- Ahmad Luqman-Fatah
- , Yuzo Watanabe
- & Tomoichiro Miyoshi
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Article
| Open AccessArabidopsis DXO1 activates RNMT1 to methylate the mRNA guanosine cap
Arabidopsis DXO1 is a member of the eukaryotic DXO family of decapping enzymes for NAD-capped RNAs. Here the authors show that DXO1 is an essential component in canonical m7G capping of mRNA and activates RNMT1 which methylates the guanosine cap to form the m7G cap.
- Chen Xiao
- , Kaien Li
- & Yiji Xia
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Article
| Open AccessHuman mitochondria require mtRF1 for translation termination at non-canonical stop codons
The mammalian mitochondrial genome contains two noncanonical stop codons, AGA and AGG. Here, the authors show that mtRF1, a mitochondrial protein of unknown function, triggers translation termination at AGA or AGG, placing mtRF1 among mitochondrial translation factors.
- Annika Krüger
- , Cristina Remes
- & Joanna Rorbach
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Article
| Open AccessExon junction complex shapes the m6A epitranscriptome
Here the authors show the exon junction complex (EJC) component, EIF4A3, locally restricts METTL3- mediated mRNA methylation at exon junctions to explain the observed widespread enrichment of m6A modification in 3’ untranslated regions.
- Xin Yang
- , Robinson Triboulet
- & Richard I. Gregory
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Article
| Open AccessStructural basis of sequence-specific RNA recognition by the antiviral factor APOBEC3G
Interaction between APOBEC3G and RNA is critical for its antiviral function. Here, the authors report four co-crystal structures of rhesus macaque APOBEC3G and RNA, demonstrating unpaired AA and GA dinucleotide motifs are preferentially recognized.
- Hanjing Yang
- , Kyumin Kim
- & Xiaojiang S. Chen
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Article
| Open AccessThe PNUTS-PP1 complex acts as an intrinsic barrier to herpesvirus KSHV gene expression and replication
The PNUTS-PP1 complex directly binds to RNA, and interacts with polymerase II and RNA processing factors to control transcriptional elongation rates and slow polymerase II after polyadenylation sites to promote termination. Using a genome-wide CRISPR screen, Devlin et al. identify this complex as a critical suppressor of herpesvirus KSHV gene expression. They further provide evidence that PNUTS-PP1 controls elongation both downstream and upstream of polyadenylation sites on specific viral genes.
- Anne M. Devlin
- , Ashutosh Shukla
- & Nicholas K. Conrad
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Article
| Open AccessAltered tRNA processing is linked to a distinct and unusual La protein in Tetrahymena thermophila
La proteins are conserved factors critical for the maturation of RNA polymerase III transcripts. In the ciliate T. thermophila and related alveolates, La proteins have a novel domain arrangement and are linked to a distinct pre-tRNA processing pathway.
- Kyra Kerkhofs
- , Jyoti Garg
- & Mark A. Bayfield
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Article
| Open AccessRNA-controlled nucleocytoplasmic shuttling of mRNA decay factors regulates mRNA synthesis and a novel mRNA decay pathway
Nucleocytoplasmic shuttling of several yeast mRNA decay factors regulates transcription and initiates a novel mRNA decay pathway; shuttling is controlled by the decaying RNA and is critical for coping with environmental changes.
- Shiladitya Chattopadhyay
- , Jose Garcia-Martinez
- & Mordechai Choder
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Article
| Open AccessPrematurely terminated intron-retaining mRNAs invade axons in SFPQ null-driven neurodegeneration and are a hallmark of ALS
Nuclear depletion and cytoplasmic accumulation of splicing factor SFPQ are hallmarks of ALS. Here the authors demonstrate a relationship between loss of SFPQ and the emergence in neurites of intron-retaining mRNAs enriched in ALS models and tissues.
- Richard Taylor
- , Fursham Hamid
- & Corinne Houart
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Article
| Open AccessA nascent peptide code for translational control of mRNA stability in human cells
Here, the authors measure the mRNA levels of thousands of coding sequence motifs in human cells to find that nascent peptides with a combination of β-strand structures and bulky and positively charged sequences reduce mRNA levels by slowing translation.
- Phillip C. Burke
- , Heungwon Park
- & Arvind Rasi Subramaniam
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Article
| Open AccessCryo-EM reveals the architecture of the PELP1-WDR18 molecular scaffold
PELP1 is a large scaffolding protein implicated in many cellular activities, including ribosome assembly as part of the Rix1 complex, comprising PELP1, WDR18, TEX10 and other components. Here, authors present the cryo-EM structure of PELP1 in complex with its binding partner WDR18, revealing the architecture of PELP1's numerous signaling motifs.
- Jacob Gordon
- , Fleur L. Chapus
- & Robin E. Stanley
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Article
| Open AccessMETTL14 is required for exercise-induced cardiac hypertrophy and protects against myocardial ischemia-reperfusion injury
The benefit of regular exercise on the heart has been well documented but the role of RNA m6A modification in exercise-induced cardiac remodelling remains largely unknown. In this study, the authors report that METTL14 plays an important role in RNA m6A modification in exercise-induced physiological cardiac hypertrophy.
- Lijun Wang
- , Jiaqi Wang
- & Junjie Xiao
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Article
| Open AccessStructural basis for sequence-independent substrate selection by eukaryotic wobble base tRNA deaminase ADAT2/3
The deamination of all adenosines in the wobble base position is essential to empower the individual tRNA to decode several codons. Here, the authors present the cryo-EM structure of the tRNA-bound ADAT2/3 deaminase, revealing how the geometry-specific enzyme acquiesces sequence-divergent tRNAs to its active site.
- Luciano G. Dolce
- , Aubree A. Zimmer
- & Eva Kowalinski
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Article
| Open Access2′–5′ oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability
Maintaining optimal eNOS levels is important during cardiovascular events, although little is known regarding the mechanism of eNOS protection. Here, the authors show a regulatory role of endothelial OASL1 in maintaining eNOS mRNA stability and vascular biology under atheroprone conditions.
- Tae Kyeong Kim
- , Sejin Jeon
- & Goo Taeg Oh
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Article
| Open AccessSubcellular spatial transcriptomics identifies three mechanistically different classes of localizing RNAs
In this study the authors identify localized RNAs in the Drosophila follicular epithelium by spatial transcriptomics and through genetic analyses determine canonical and translation-based mechanisms underlying basal and apical RNA localization.
- Lucia Cassella
- & Anne Ephrussi
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Article
| Open AccessThe coilin N-terminus mediates multivalent interactions between coilin and Nopp140 to form and maintain Cajal bodies
Cajal bodies are membraneless organelles scaffolded by coilin protein. Here, coilin–coilin and coilin–Nopp140 interaction sites are identified and perturbed, revealing coilin’s capacity to form long fibrils and be remodeled into spherical structures.
- Edward Courchaine
- , Sara Gelles-Watnick
- & Karla M. Neugebauer
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Article
| Open AccessSequential action of a tRNA base editor in conversion of cytidine to pseudouridine
C-to-Ψ conversion is a previously uncharacterized form of base editing. Here, the authors describe how the TrcP enzyme catalyzes this process in a stepwise fashion and how this editing process is controlled by a network of modifications and nutrient availability to optimize translation efficiency.
- Satoshi Kimura
- , Veerasak Srisuknimit
- & Matthew K. Waldor
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Article
| Open AccessThe solution structure of Dead End bound to AU-rich RNA reveals an unusual mode of tandem RRM-RNA recognition required for mRNA regulation
The authors report an unusual mode of AU-rich RNA recognition by the RNA recognition motifs of DND1, a protein essential for germline development, in a 27.5 kDa NMR structure and provide additional insight on DND1 function from cell-based experiments.
- Malgorzata M. Duszczyk
- , Harry Wischnewski
- & Frédéric H.-T. Allain
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Article
| Open AccessAutophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA
The role of eiptranscriptomic modifications in autophagy is unclear. Here, the authors show that the m6A reader YTHDF3 functions as a nutrient responder to recognize upregulated m6A modification, promoting FOXO3 translation to subsequently initiate autophagy.
- WeiChao Hao
- , MeiJuan Dian
- & Dong Xiao
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Article
| Open AccessANGEL2 phosphatase activity is required for non-canonical mitochondrial RNA processing
A subset of mitochondrial transcripts is not flanked by tRNAs and thus does not conform to the canonical mode of processing. Here, Clemente et al. demonstrate that phosphatase activity of ANGEL2 is required for correct processing of these transcripts.
- Paula Clemente
- , Javier Calvo-Garrido
- & Anna Wredenberg
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Article
| Open AccessStructural insights into molecular mechanism for N6-adenosine methylation by MT-A70 family methyltransferase METTL4
Here the authors combine functional and structural work to show that METTL4 functions as U2 snRNA m6Am RNA methyltransferase supporting N6-methylation of 2’-O-methyladenosine in Arabidopsis.
- Qiang Luo
- , Jiezhen Mo
- & Jinbiao Ma
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Article
| Open AccessHigh-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance
Multiple alternative splicing events in CD19 mRNA have been associated with resistance/relapse to CD19 CAR-T therapy in patients with B cell malignancies. Here, by combining patient data and a high-throughput mutagenesis screen, the authors identify single point mutations and RNA-binding proteins that can control CD19 splicing and be associated with CD19 CAR-T therapy resistance.
- Mariela Cortés-López
- , Laura Schulz
- & Julian König
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Article
| Open AccessAdar-mediated A-to-I editing is required for embryonic patterning and innate immune response regulation in zebrafish
Additional roles for A-to-I editing of RNA continue to be uncovered. Niescierowicz et al. report prevalent A-to-I editing in the zebrafish transcriptome, and the distinct maternal and zygotic functions of the editing enzyme Adar in embryonic patterning and in the regulation of innate immune response, respectively.
- Katarzyna Niescierowicz
- , Leszek Pryszcz
- & Cecilia Winata
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Article
| Open AccessDiverse cell-specific patterns of alternative polyadenylation in Drosophila
Single cell data provides cellular resolution on gene expression, but is rarely mined for isoforms. Analysis of 3' isoforms across ~250 Drosophila cell types reveals the cellular bases for numerous tissue-specific 3' programs, identifies new 3' programs, and nominates candidate trans-acting factors
- Seungjae Lee
- , Yen-Chung Chen
- & Eric C. Lai
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Article
| Open AccessTENT2, TUT4, and TUT7 selectively regulate miRNA sequence and abundance
The authors reveal insights into miRNA tailing specificity of TENTs and their effect on miRNA levels by combinatory KOs of TENT2, TUT4 and TUT7. They show uridylation is linked to TENT2 and identify non-redundant functions between TUT4 and TUT7.
- Acong Yang
- , Xavier Bofill-De Ros
- & Shuo Gu
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Article
| Open AccessThe nucleolus is the site for inflammatory RNA decay during infection
The nucleolus is the traditional site for ribosomal RNA biogenesis. Here, the authors find that the nucleolus is a site of inflammatory pre-mRNA turnover and elucidated how immune homeostasis can be maintained by controlling inflammatory gene expression.
- Taeyun A. Lee
- , Heonjong Han
- & Boyoun Park
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Article
| Open AccessOligodendrocyte differentiation alters tRNA modifications and codon optimality-mediated mRNA decay
Mutations in tRNA processing factors can lead to myelin disorders. This study shows that differentiated oligodendrocytes, cells that make the myelin, are characterized by different tRNA modifications and mRNA decay compared to their precursor cells.
- Sophie Martin
- , Kevin C. Allan
- & Jeff Coller
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Article
| Open AccessStructural analysis of Red1 as a conserved scaffold of the RNA-targeting MTREC/PAXT complex
Unwanted RNA transcripts are targeted for degradation by nuclear complexes such as MTREC/PAXT. Here, the authors structurally and functionally characterized three interfaces of the scaffold protein Red1, providing mechanistic insights into conserved features of MTREC/PAXT architecture.
- Anne-Emmanuelle Foucher
- , Leila Touat-Todeschini
- & Jan Kadlec
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Article
| Open AccessHeterogeneous nuclear ribonucleoprotein U (HNRNPU) safeguards the developing mouse cortex
HNRNPU is an RNA splicing protein associated with brain disorders such as early onset seizures. Here they show that HNRNPU functions to maintain neural progenitors and their progeny by regulating splicing of key neuronal genes.
- Tamar Sapir
- , Aditya Kshirsagar
- & Orly Reiner
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Article
| Open AccessN6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis
Ma et al. profile the dynamic landscape of m6A during pancreatic differentiation, and identify ALKBH5 as an essential m6A regulator supporting pancreatic differentiation, indicating a role for m6A-mediated mRNA metabolism in cell-fate specification.
- Xiaojie Ma
- , Jie Cao
- & Saiyong Zhu
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Article
| Open AccessTRIM24 is an insulin-responsive regulator of P-bodies
Insulin promotes hepatic lipogenesis, though underlying regulation remains unclear. Here the authors show that insulin translocates TRIM24 from the nucleus into cytosolic P-bodies to stabilise hepatic Pparγ mRNA, and that inactivation of TRIM24 promotes Pparγ degradation and alleviates hepatosteatosis.
- Wen Wei
- , Qiaoli Chen
- & Shuai Chen
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Article
| Open AccessLimited effects of m6A modification on mRNA partitioning into stress granules
Recent studies proposed that m6A modification in mammalian mRNAs increases their recruitment to stress granule. However, here the authors observed that m6A modification has a limited effect on mRNA entry into stress granules.
- Anthony Khong
- , Tyler Matheny
- & Roy Parker