Genes & development最新文献_第8页

A new perspective on ATR's role in translesion synthesis. ATR在翻译合成中的作用的新视角。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-07-01 DOI: 10.1101/gad.353773.126

Laura A Lindsey-Boltz, Aziz Sancar

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 7.4 1区生物学

Genes & development Pub Date : 2026-06-01 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

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 7.4 1区生物学

Genes & development Pub Date : 2026-06-01 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":"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":"956-977"},"PeriodicalIF":7.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224856/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The eukaryotic homology search complex distorts donor DNA structure to probe for homology. 真核生物同源搜索复合物扭曲供体DNA结构以探测同源性。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-06-01 DOI: 10.1101/gad.353376.125

Mitchell V Woodhouse, Jingyi Hu, Meiling Wu, Jin Qian, James T Inman, Michelle D Wang, J Brooks Crickard

{"title":"The eukaryotic homology search complex distorts donor DNA structure to probe for homology.","authors":"Mitchell V Woodhouse, Jingyi Hu, Meiling Wu, Jin Qian, James T Inman, Michelle D Wang, J Brooks Crickard","doi":"10.1101/gad.353376.125","DOIUrl":"10.1101/gad.353376.125","url":null,"abstract":"Homologous recombination (HR) is a DNA double-strand break repair pathway that facilitates genetic exchange and protects damaged replication forks during DNA synthesis. As a template-based repair process, the successful repair of a double-strand break depends on locating suitable homology from a donor DNA sequence elsewhere in the genome. In eukaryotes, Rad51 catalyzes the homology search in coordination with the ATP-dependent motor protein Rad54. The mechanism by which these two proteins regulate forces on dsDNA substrates during homology search remains unknown. Here, we have utilized single-molecule magnetic tweezers and optical trapping methods to monitor remodeling of the DNA template during the homology search. We found that the activity of Rad51 and Rad54 remodels the donor DNA substrate to control the association and dissociation of Rad51-ssDNA filaments in the absence of DNA homology. The mechanism is through the generation of short, isolated, underwound DNA loops extruded by the homology search complex composed of Rad51 and Rad54. Finally, failure of Rad54 to act processively disrupts target selection in vivo. This study provides a basic understanding of how motorized homology search manipulates the donor DNA during the search for a suitable repair template.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"832-851"},"PeriodicalIF":7.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13119058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147627539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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 7.4 1区生物学

Genes & development Pub Date : 2026-06-01 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":"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":"912-935"},"PeriodicalIF":7.4,"publicationDate":"2026-06-01","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

Structure, function, regulation, evolution, and therapeutic implications of PARP14. PARP14的结构、功能、调控、进化及其治疗意义。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-06-01 DOI: 10.1101/gad.353495.125

Pulak Kar, Nina Đukić, Dragana Ahel, Ivan Ahel

{"title":"Structure, function, regulation, evolution, and therapeutic implications of PARP14.","authors":"Pulak Kar, Nina Đukić, Dragana Ahel, Ivan Ahel","doi":"10.1101/gad.353495.125","DOIUrl":"10.1101/gad.353495.125","url":null,"abstract":"ADP-ribosylation (ADPr) is a posttranslational modification conserved across all domains of life that regulates a wide variety of processes. Among ADP-ribosyl transferases (ARTs) in humans, PARP14 has emerged as a key regulator involved in antiviral defense, inflammation, and DNA damage response. Recent studies have uncovered its dynamic and versatile roles in modulating DNA replication stress and DNA repair, positioning it at the intersection of genomic stability and immune regulation. Despite growing insights into its molecular functions, many aspects of PARP14-mediated signaling remain elusive. In this perspective, we explore the fundamental and emerging biological features of PARP14, highlighting its structure, function, evolution, and roles in cellular homeostasis and disease. Additionally, we discuss recent advances in targeting PARP14 for therapeutic intervention, particularly in oncology and immunology. A deeper mechanistic understanding of PARP14 function may inform the development of novel therapeutic strategies that exploit its regulatory network for clinical benefit.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"780-795"},"PeriodicalIF":7.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147369387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Defective HNF1A hinders GLI3 processing favoring duodenal versus pancreatic fate, thus leading to intestinal elongation in vivo. 缺陷的HNF1A阻碍了GLI3的加工，有利于十二指肠与胰腺的命运，从而导致体内肠道伸长。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-06-01 DOI: 10.1101/gad.353153.125

Lucas Unger, Ulrik Larsen, Thomas Aga Legøy, Md Kaykobad Hossain, June Helen Gudmestad, Amanda Friestad, Shayla Sharmine, Pål Rasmus Njølstad, Helge Ræder, Pedro Luis Herrera, Luiza Ghila, Simona Chera

{"title":"Defective HNF1A hinders GLI3 processing favoring duodenal versus pancreatic fate, thus leading to intestinal elongation in vivo.","authors":"Lucas Unger, Ulrik Larsen, Thomas Aga Legøy, Md Kaykobad Hossain, June Helen Gudmestad, Amanda Friestad, Shayla Sharmine, Pål Rasmus Njølstad, Helge Ræder, Pedro Luis Herrera, Luiza Ghila, Simona Chera","doi":"10.1101/gad.353153.125","DOIUrl":"10.1101/gad.353153.125","url":null,"abstract":"Regulatory circuits driving regional cell fate specification and lineage restriction decisions are not fully understood. The molecular mechanisms by which Hedgehog signaling controls lineage segregation in the posterior foregut remain unclear. Here, we employed bulk and single-cell transcriptomics, microscopy, physiology, and genetic cell tracing in differentiating human induced pluripotent stem cells and mouse transgenic models to uncover an essential autoregulatory loop between Hnf1a and Hedgehog signaling. Hnf1a abrogation initiates a domino effect leading to a drift in foregut cell specification toward duodenal cell identity instead of pancreatic fate. This was replicated in vivo in mice. We show that a common dominant negative Hnf1a mutation disrupts GLI3 processing by cilium proteins in the posterior foregut, thus impeding its own upregulation in response to Hedgehog signaling inhibition. In the context of this defective loop, we identified a network of deregulated selector genes responsible for the lineage segregation changes. These may be relevant for changes in the liver, pancreas, and gut seen in patients with mutations in HNF1A.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"805-831"},"PeriodicalIF":7.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147520424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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 7.4 1区生物学

Genes & development Pub Date : 2026-06-01 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":"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":"852-872"},"PeriodicalIF":7.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224860/pdf/","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":"OA","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 7.4 1区生物学

Genes & development Pub Date : 2026-06-01 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":"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":"873-892"},"PeriodicalIF":7.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224869/pdf/","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":"OA","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 7.4 1区生物学

Genes & development Pub Date : 2026-06-01 DOI: 10.1101/gad.353709.126

Julie Warin, Anne Grapin-Botton

引用次数: 0