Genes & development最新文献_第2页

IF 7.7 1区生物学

Genes & development Pub Date : 2026-05-04 DOI: 10.1101/gad.353649.126

Amy E Pasquinelli

引用次数: 0

DDX3X-mediated translation of structured cardiac mRNAs is essential for female heart development. ddx3x介导的结构化心脏mrna翻译对女性心脏发育至关重要。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-27 DOI: 10.1101/gad.353320.125

Kayla K Mason, Seohyun K Park, James I Emerson, Yao Wei Lu, Da-Zhi Wang, William F Marzluff, Frank L Conlon

{"title":"DDX3X-mediated translation of structured cardiac mRNAs is essential for female heart development.","authors":"Kayla K Mason, Seohyun K Park, James I Emerson, Yao Wei Lu, Da-Zhi Wang, William F Marzluff, Frank L Conlon","doi":"10.1101/gad.353320.125","DOIUrl":"https://doi.org/10.1101/gad.353320.125","url":null,"abstract":"Sex differences influence congenital heart disease (CHD) development, yet underlying molecular mechanisms remain largely unclear. We demonstrate that the X-linked RNA helicase DDX3X associates in the heart with ribosomal subunit proteins, and eCLIP mapping reveals its preferential binding to cardiac mRNAs with long, structured 5' untranslated regions (UTRs) that can hinder translation. Using a cardiomyocyte-specific mouse Ddx3x knockout model, we show that female embryos lacking Ddx3x die at midgestation from heart failure due to impaired translation of key cardiac regulators, whereas male littermates survive. Ribosome profiling and proteomics demonstrate that DDX3X is required for efficient translation of female differential cardiac mRNAs. Reporter assays confirm that translation of essential cardiac genes such as Srf and Rcor2 depends on their 5' UTRs and requires DDX3X. These findings uncover a sex-specific posttranscriptional mechanism by which DDX3X safeguards female heart development through selective mRNA translation, providing insight into how X-linked dosage-sensitive regulators contribute to CHD.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147768938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MLL4/KMT2D histone methyltransferase and JUNB cooperate in a feed-forward loop to support AP-1-dependent TGF-β signaling. MLL4/KMT2D组蛋白甲基转移酶和JUNB在前馈环路中合作，支持ap -1依赖性TGF-β信号传导。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-24 DOI: 10.1101/gad.353313.125

Timothy En Haw Chan, Md Saiful Islam, Omid Fotouhi, Mert Bozkurt, Sheikh Nizamuddin, Katrin M Schüle, Sebastian J Arnold, H T Marc Timmers

{"title":"MLL4/KMT2D histone methyltransferase and JUNB cooperate in a feed-forward loop to support AP-1-dependent TGF-β signaling.","authors":"Timothy En Haw Chan, Md Saiful Islam, Omid Fotouhi, Mert Bozkurt, Sheikh Nizamuddin, Katrin M Schüle, Sebastian J Arnold, H T Marc Timmers","doi":"10.1101/gad.353313.125","DOIUrl":"https://doi.org/10.1101/gad.353313.125","url":null,"abstract":"Transforming growth factor β (TGF-β) signaling is a highly pleiotropic pathway with an important role in development, homeostasis, and cancer. Chromatin regulators contribute to the regulation of TGF-β-responsive transcription. The requirement of subunits of the MLL3/MLL4 histone methyltransferase complexes for TGF-β responses has been reported. However, their exact roles are not fully understood. To investigate the functions of these complexes, we employed CRISPR/Cas9 genome editing to inactivate the KMT2C/MLL3 or KMT2D/MLL4 genes in human diploid epithelial cells. Time-course RNA-seq experiments revealed the requirement of MLL4 but not of MLL3 for TGF-β transcriptional responses. CUT&RUN experiments showed that MLL4 binding increases after TGF-β treatment and is especially enriched at AP-1 transcription factor binding sites. Interestingly, TGF-β-induced chromatin binding of MLL4 correlates with increases in H3K27ac but not in H3K4me1 modifications. Furthermore, TGF-β treatment sets off SMAD2-induced JUNB expression, which forms a feed-forward loop with MLL4. By inhibiting the activities of AP-1, the BAF chromatin remodeler, or the CBP/p300 histone acetyltransferase, we found that AP-1 binding and these chromatin regulators are all necessary for TGF-β induction of MLL4 binding and transcriptional activation of its genomic targets. Taken together, our study reveals distinctive roles for the MLL3 and MLL4 paralogs in the transcriptional response to TGF-β. In contrast to MLL3, MLL4 forms a feed-forward loop of JUNB, the BAF complex, and CBP/p300 to sustain transcription activation by TGF-β.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147768989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neural stem cell epigenomes and fate bias are temporally coordinated during mouse cortical development. 神经干细胞表观基因组和命运偏差在小鼠皮层发育过程中是暂时协调的。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-22 DOI: 10.1101/gad.353090.125

Yonatan Shapira, Florian Noack, Silvia Vangelisti, Faye Chong, Aviezer Lifshitz, Amos Tanay, Boyan Bonev

{"title":"Neural stem cell epigenomes and fate bias are temporally coordinated during mouse cortical development.","authors":"Yonatan Shapira, Florian Noack, Silvia Vangelisti, Faye Chong, Aviezer Lifshitz, Amos Tanay, Boyan Bonev","doi":"10.1101/gad.353090.125","DOIUrl":"https://doi.org/10.1101/gad.353090.125","url":null,"abstract":"During cortical development, neural stem cells (NSCs) combine self-renewal with the sequential production of different subtypes of projection neurons as well as glia cells. How the NSC epigenome accommodates this over time remains unresolved. Here, we address this gap by multimodal epigenomic profiling of mouse cortical development across six time points and five embryonic days. Single-cell gene expression and temporal modeling reveal that NSC self-renewal is not homeostatic, showing progressively stronger astrocytic preference over time. Chromosome accessibility, DNA methylation, and Hi-C show that this process involves major reorganization of the NSC epigenome. A model combining transcription factor motif affinities with epigenetic features, as well as integration of the results with a reporter assay in vivo, show that activation of the NSC neuronal fate regulatory program may be affected by a changing epigenome. Collectively, our findings uncover temporal epigenomic reprogramming that underlies the evolving differentiation potential of NSCs, providing insights into the intrinsic and extrinsic mechanisms that pattern cortical lineages.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147768953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modeling medulloblastoma pathogenesis and treatment in human cerebellar organoids. 人类小脑类器官成神经管细胞瘤的发病机制和治疗模型。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-22 DOI: 10.1101/gad.353292.125

Thomas Willott, James G Nicholson, Xinyu Zhang, Yunchen Xiao, Olumide Ogunbiyi, Benjamin Draper, Talisa Mistry, Laura K Donovan, Ashirwad Merve, Nicolae Radu Zabet, Sara Badodi, Silvia Marino

{"title":"Modeling medulloblastoma pathogenesis and treatment in human cerebellar organoids.","authors":"Thomas Willott, James G Nicholson, Xinyu Zhang, Yunchen Xiao, Olumide Ogunbiyi, Benjamin Draper, Talisa Mistry, Laura K Donovan, Ashirwad Merve, Nicolae Radu Zabet, Sara Badodi, Silvia Marino","doi":"10.1101/gad.353292.125","DOIUrl":"https://doi.org/10.1101/gad.353292.125","url":null,"abstract":"Medulloblastoma (MB) groups 3 and 4 arise from human-specific developmental contexts that remain experimentally inaccessible, limiting mechanistic insight into tumor initiation. We generated cerebellar organoids (CbOs) from expanded potential stem cells (EPSCs) and performed integrated single-cell transcriptomic and DNA methylation analyses, revealing discrete human rhombic lip progenitor populations whose developmental programs align with group 3- and group 4-associated lineages. Using c-MYC overexpression as an initiating oncogenic event, we demonstrated that these lineage-restricted progenitors are susceptible to neoplastic transformation, generating tumors with group 3 MB molecular features in vitro and in vivo. We further established a CbO-MB coculture system that preserves malignant and nonmalignant cellular compartments, hence enabling interrogation of tumor-microenvironment interactions and providing simultaneous readouts of antitumor efficacy and cerebellar toxicity upon drug treatment. Receptor-ligand modeling in this system identifies TGFβ paracrine signaling as a microenvironmental pathway supporting MB growth, which we validated pharmacologically. Further analyses of cocultured MB cells revealed a myogenic differentiation program enriched in MYC-driven MB and recurrent disease, which is associated with poorer prognosis. Together, this work establishes a collection of CbO models for studying group 3/4 MB initiation, growth, and microenvironmental dependencies and provides a tractable platform for further mechanistic and therapeutic investigation of these tumors.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147768976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rethinking HNF1A-MODY: HNF1A at the crossroads of development and multiorgan metabolic disease. 重新思考HNF1A- mody: HNF1A在发育和多器官代谢疾病的十字路口。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-22 DOI: 10.1101/gad.353709.126

Julie Warin, Anne Grapin-Botton

引用次数: 0

The microprotein SMIM26 connects metabolite transporters of the outer and inner mitochondrial membranes and is essential for respiratory chain function. 微蛋白SMIM26连接线粒体内外膜的代谢物转运体，对呼吸链功能至关重要。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-16 DOI: 10.1101/gad.353272.125

Kevin Heizler, Anastasia Chugunova, Mara Hofmann, Michaela Prochazkova, Jan Procházka, Hung Ho-Xuan, Joerg Fallmann, Karel Stejskal, Gabriela Krssakova, Stefanie Bader, Erman Kocak, Dogukan Yasar, Patricia Luckner, Gerhard Lehmann, Julian Köngeter, Marisa Riester, Elisabeth Roitinger, Christian Wetzel, Sven Diederichs, Radislav Sedlacek, Astrid Bruckmann, J Christof M Gebhardt, Andrea Pauli, Gunter Meister

{"title":"The microprotein SMIM26 connects metabolite transporters of the outer and inner mitochondrial membranes and is essential for respiratory chain function.","authors":"Kevin Heizler, Anastasia Chugunova, Mara Hofmann, Michaela Prochazkova, Jan Procházka, Hung Ho-Xuan, Joerg Fallmann, Karel Stejskal, Gabriela Krssakova, Stefanie Bader, Erman Kocak, Dogukan Yasar, Patricia Luckner, Gerhard Lehmann, Julian Köngeter, Marisa Riester, Elisabeth Roitinger, Christian Wetzel, Sven Diederichs, Radislav Sedlacek, Astrid Bruckmann, J Christof M Gebhardt, Andrea Pauli, Gunter Meister","doi":"10.1101/gad.353272.125","DOIUrl":"https://doi.org/10.1101/gad.353272.125","url":null,"abstract":"Microproteins represent a class of short polypeptides with very diverse cellular functions. Microproteins frequently escape proteomics-based identification, making the extent and potential functions of small proteins largely elusive. Some microproteins originate from transcripts that are annotated as long noncoding RNAs (lncRNAs). Here, we functionally characterize SMIM26, a microprotein localized to mitochondria. In biochemical and single-molecule tracking studies, we found that SMIM26 interacts with VDAC1/2 in the outer mitochondrial membrane and with SLC25A6 in the inner mitochondrial membrane. It spans the intermembrane space and is phosphorylated at distinct residues. Knockout cells are viable, but respiratory chain activity is strongly reduced. Interestingly, knockout mice are not viable and die at early developmental stages. Zebrafish homozygous smim26 mutants are viable but show reduced fitness and survival compared with their wild-type or heterozygous siblings. Consistent with the mitochondrial phenotype in cell lines, respiration is also reduced in homozygous zebrafish embryos. Our work suggests that SMIM26 coordinates metabolite transport through the inner and outer mitochondrial membranes and is essential for respiratory chain function in vivo.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147698489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

KLF18 is a necessary component of the DUX4-initiated transcriptional network and a candidate locus for phenotypic diversity. KLF18是dux4启动的转录网络的必要组成部分，也是表型多样性的候选位点。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-15 DOI: 10.1101/gad.353253.125

Danielle C Hamm, Aidan B O'Donnell, Sean R Bennett, Richard J L F Lemmers, Patrick J van der Vliet, Silvère M van der Maarel, Stephen J Tapscott

{"title":"KLF18 is a necessary component of the DUX4-initiated transcriptional network and a candidate locus for phenotypic diversity.","authors":"Danielle C Hamm, Aidan B O'Donnell, Sean R Bennett, Richard J L F Lemmers, Patrick J van der Vliet, Silvère M van der Maarel, Stephen J Tapscott","doi":"10.1101/gad.353253.125","DOIUrl":"https://doi.org/10.1101/gad.353253.125","url":null,"abstract":"DUX4 initiates the first wave of zygotic genome activation (ZGA) in the human embryo, and its misexpression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). However, other factors that help regulate ZGA-like transcription in human development and disease are still not fully understood. Here we identify Krüppel-like factor 18 (KLF18) as a component of a DUX4 feed-forward network that is necessary for expression of KLF17 and a subset of DUX4-regulated totipotency-associated genes. We mapped the genome-wide binding profile of KLF18 downstream from DUX4 and showed that its activity is influenced by DUX4 and chromatin accessibility. We found that in contrast to the rodent ortholog, human KLF18 has a predicted β-solenoid structure composed of a variable number of tandem repeats (VNTR) with multiple different structural variants in the human population. Expression of different KLF18 variants in combination with DUX4 showed similar transcriptional activity, whereas assessment of KLF18 structural variants in individuals with FSHD1 showed inconsistent association with disease severity that requires further study as a modifier locus. Together, these findings establish the polymorphic transcription factor KLF18 as a critical component of a DUX4-initiated feed-forward network and a candidate locus for human diversity.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147689724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DAXX directs dual modes of H3.4-to-H3.3 histone replacement in the male germline. DAXX在男性种系中指导h3.4 - h3.3组蛋白替代的双重模式。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-14 DOI: 10.1101/gad.353435.125

Yu-Han Yeh, Mengwen Hu, Kai Otsuka, Brooke M Alger, Shruti S Nene, Han Wang, So Maezawa, Satoshi H Namekawa

引用次数: 0

A dual role for cGAS in shaping cellular and organismal responses to genomic instability. cGAS在塑造细胞和生物体对基因组不稳定性的反应中的双重作用。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-04-14 DOI: 10.1101/gad.352760.125

Marva Bergman, Uri Goshtchevsky, Tehila Atlan, Gwendoline Astre, Ryan Halabi, Hosniyah El Ayoubi, Eitan Moses, Aaron J J Lemus, Bérénice A Benayoun, Yehuda Tzfati, Ido Ben-Ami, Itamar Harel

{"title":"A dual role for cGAS in shaping cellular and organismal responses to genomic instability.","authors":"Marva Bergman, Uri Goshtchevsky, Tehila Atlan, Gwendoline Astre, Ryan Halabi, Hosniyah El Ayoubi, Eitan Moses, Aaron J J Lemus, Bérénice A Benayoun, Yehuda Tzfati, Ido Ben-Ami, Itamar Harel","doi":"10.1101/gad.352760.125","DOIUrl":"https://doi.org/10.1101/gad.352760.125","url":null,"abstract":"Mutations in DNA damage repair (DDR) genes lead to genomic instability, driving a range of degenerative syndromes. In addition to promoting mutation accumulation, unrepaired DNA damage can leak into the cytosol and activate innate immune-sensing pathways, particularly the cGAS-STING axis. However, the extent to which cGAS causally contributes to organismal pathology in DDR syndromes in vivo remains unresolved. Here, we genetically model ataxia telangiectasia (A-T) and Bloom syndrome in the short-lived turquoise killifish (Nothobranchius furzeri) and demonstrate that genetic disruption of cgas in the A-T model partially ameliorates germline failure, hepatic senescence, and cerebellar neuroinflammation. Unexpectedly, cgas loss also reversed cellular hallmarks of genome instability, including reduced micronuclei, improved telomere integrity, and restored H3K9me3-marked heterochromatin landscape, consistent with STING-independent nuclear functions of cGAS that influence DNA repair and chromatin. Together, these data identify cGAS as a context-dependent amplifier of DDR pathology acting through canonical inflammatory signaling and noncanonical nuclear mechanisms that shape genome stability. Accordingly, our findings support pharmacological cGAS inhibition as a potential strategy for DDR syndromes in settings of chronic DNA damage while highlighting that cgas loss in an otherwise naive background exacerbates pathology and genomic instability, underscoring its essential role in normal physiology.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147689641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0