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Pan-cellular organelles and suborganelles—from common functions to cellular diversity? Genes Dev. (IF 10.5) Pub Date : 2024-03-14 Rico Schieweck, Magdalena Götz
Cell diversification is at the base of increasing multicellular organism complexity in phylogeny achieved during ontogeny. However, there are also functions common to all cells, such as cell division, cell migration, translation, endocytosis, exocytosis, etc. Here we revisit the organelles involved in such common functions, reviewing recent evidence of unexpected differences of proteins at these organelles
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A serine metabolic enzyme is flexing its muscle to help repair skeletal muscle Genes Dev. (IF 10.5) Pub Date : 2024-03-14 Benjámin R. Baráth, Laszlo Nagy
Metabolic reprogramming of stem cells is a targetable pathway to control regeneration. Activation of stem cells results in down-regulation of oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) and turns on glycolysis to provide fuel for proliferation and specific signaling events. How cell type-specific events are regulated is unknown. In this issue of Genes & Development Ciuffoli and
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ADNP modulates SINE B2-derived CTCF-binding sites during blastocyst formation in mice Genes Dev. (IF 10.5) Pub Date : 2024-03-13 Wen Wang, Rui Gao, Dongxu Yang, Mingli Ma, Ruge Zang, Xiangxiu Wang, Chuan Chen, Xiaochen Kou, Yanhong Zhao, Jiayu Chen, Xuelian Liu, Jiaxu Lu, Ben Xu, Juntao Liu, Yanxin Huang, Chaoqun Chen, Hong Wang, Shaorong Gao, Yong Zhang, Yawei Gao
CTCF is crucial for chromatin structure and transcription regulation in early embryonic development. However, the kinetics of CTCF chromatin occupation in preimplantation embryos have remained unclear. In this study, we used CUT&RUN technology to investigate CTCF occupancy in mouse preimplantation development. Our findings revealed that CTCF begins binding to the genome prior to zygotic genome activation
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Coordination of histone chaperones for parental histone segregation and epigenetic inheritance Genes Dev. (IF 10.5) Pub Date : 2024-03-13 Yimeng Fang, Xu Hua, Chun-Min Shan, Takenori Toda, Feng Qiao, Zhiguo Zhang, Songtao Jia
Chromatin-based epigenetic memory relies on the accurate distribution of parental histone H3–H4 tetramers to newly replicated DNA strands. Mcm2, a subunit of the replicative helicase, and Dpb3/4, subunits of DNA polymerase ε, govern parental histone H3–H4 deposition to the lagging and leading strands, respectively. However, their contribution to epigenetic inheritance remains controversial. Here, using
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A maternal-effect Padi6 variant causes nuclear and cytoplasmic abnormalities in oocytes, as well as failure of epigenetic reprogramming and zygotic genome activation in embryos Genes Dev. (IF 10.5) Pub Date : 2024-03-07 Carlo Giaccari, Francesco Cecere, Lucia Argenziano, Angela Pagano, Antonio Galvao, Dario Acampora, Gianna Rossi, Bruno Hay Mele, Basilia Acurzio, Scott Coonrod, Maria Vittoria Cubellis, Flavia Cerrato, Simon Andrews, Sandra Cecconi, Gavin Kelsey, Andrea Riccio
Maternal inactivation of genes encoding components of the subcortical maternal complex (SCMC) and its associated member, PADI6, generally results in early embryo lethality. In humans, SCMC gene variants were found in the healthy mothers of children affected by multilocus imprinting disturbances (MLID). However, how the SCMC controls the DNA methylation required to regulate imprinting remains poorly
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Psat1-generated α-ketoglutarate and glutamine promote muscle stem cell activation and regeneration Genes Dev. (IF 10.5) Pub Date : 2024-03-07 Veronica Ciuffoli, Xuesong Feng, Kan Jiang, Natalia Acevedo-Luna, Kyung Dae Ko, A. Hong Jun Wang, Giulia Riparini, Mamduh Khateb, Brian Glancy, Stefania Dell'Orso, Vittorio Sartorelli
By satisfying bioenergetic demands, generating biomass, and providing metabolites serving as cofactors for chromatin modifiers, metabolism regulates adult stem cell biology. Here, we report that a branch of glycolysis, the serine biosynthesis pathway (SBP), is activated in regenerating muscle stem cells (MuSCs). Gene inactivation and metabolomics revealed that Psat1, one of the three SBP enzymes, controls
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ATF7IP2/MCAF2 directs H3K9 methylation and meiotic gene regulation in the male germline Genes Dev. (IF 10.5) Pub Date : 2024-02-21 Kris G. Alavattam, Jasmine M. Esparza, Mengwen Hu, Ryuki Shimada, Anna R. Kohrs, Hironori Abe, Yasuhisa Munakata, Kai Otsuka, Saori Yoshimura, Yuka Kitamura, Yu-Han Yeh, Yueh-Chiang Hu, Jihye Kim, Paul R. Andreassen, Kei-ichiro Ishiguro, Satoshi H. Namekawa
H3K9 trimethylation (H3K9me3) plays emerging roles in gene regulation, beyond its accumulation on pericentric constitutive heterochromatin. It remains a mystery why and how H3K9me3 undergoes dynamic regulation in male meiosis. Here, we identify a novel, critical regulator of H3K9 methylation and spermatogenic heterochromatin organization: the germline-specific protein ATF7IP2 (MCAF2). We show that
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Spore germination: Two ion channels are better than one Genes Dev. (IF 10.5) Pub Date : 2024-01-01 Patrick Eichenberger
Germination is the process by which spores emerge from dormancy. Although spores can remain dormant for decades, the study of germination is an active field of research. In this issue of Genes & Development, Gao and colleagues (pp. 31–45) address a perplexing question: How can a dormant spore initiate germination in response to environmental cues? Three distinct complexes are involved: GerA, a germinant-gated
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DNA damage remodels the MITF interactome to increase melanoma genomic instability Genes Dev. (IF 10.5) Pub Date : 2024-01-01 Romuald Binet, Jean-Philippe Lambert, Marketa Tomkova, Samuel Tischfield, Arianna Baggiolini, Sarah Picaud, Sovan Sarkar, Pakavarin Louphrasitthiphol, Diogo Dias, Suzanne Carreira, Timothy C. Humphrey, Panagis Fillipakopoulos, Richard White, Colin R. Goding
Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA damage response (DDR) programs. However, some cells (for example, in skin) are normally exposed to high levels of DNA-damaging agents. Whether such high-risk cells possess lineage-specific mechanisms that tailor DNA repair to the tissue remains largely unknown. Using melanoma
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Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma Genes Dev. (IF 10.5) Pub Date : 2024-01-01 Lucas D. Caeiro, Yuichiro Nakata, Rodrigo L. Borges, Mengsheng Zha, Liliana Garcia-Martinez, Carolina P. Bañuelos, Stephanie Stransky, Tong Liu, Ho Lam Chan, John Brabson, Diana Domínguez, Yusheng Zhang, Peter W. Lewis, Salvador Aznar Benitah, Luisa Cimmino, Daniel Bilbao, Simone Sidoli, Zheng Wang, Ramiro E. Verdun, Lluis Morey
Approximately 20% of head and neck squamous cell carcinomas (HNSCCs) exhibit reduced methylation on lysine 36 of histone H3 (H3K36me) due to mutations in histone methylase NSD1 or a lysine-to-methionine mutation in histone H3 (H3K36M). Whether such alterations of H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M can be divided
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SpoVAF and FigP assemble into oligomeric ion channels that enhance spore germination Genes Dev. (IF 10.5) Pub Date : 2024-01-01 Yongqiang Gao, Jeremy D. Amon, Anna P. Brogan, Lior Artzi, Fernando H. Ramírez-Guadiana, Joshua C. Cofsky, Andrew C. Kruse, David Z. Rudner
Bacterial spores can remain dormant for decades yet rapidly germinate and resume growth in response to nutrients. GerA family receptors that sense and respond to these signals have recently been shown to oligomerize into nutrient-gated ion channels. Ion release initiates exit from dormancy. Here, we report that a distinct ion channel, composed of SpoVAF (5AF) and its newly discovered partner protein
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Regularly spaced tyrosines in EBF1 mediate BRG1 recruitment and formation of nuclear subdiffractive clusters Genes Dev. (IF 10.5) Pub Date : 2024-01-01 Nikolay Zolotarev, Yuanting Wang, Manyu Du, Marc Bayer, Anna Grosschedl, Ibrahim Cisse, Rudolf Grosschedl
B lineage priming by pioneer transcription factor EBF1 requires the function of an intrinsically disordered region (IDR). Here, we examine the role of regularly spaced tyrosines in the IDR as potential determinants of IDR function and activity of EBF1. We found that four Y > A mutations in EBF1 reduced the formation of condensates in vitro and subdiffractive clusters in vivo. Notably, Y > A mutant
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A mutation in the low-complexity domain of splicing factor hnRNPA1 linked to amyotrophic lateral sclerosis disrupts distinct neuronal RNA splicing networks Genes Dev. (IF 10.5) Pub Date : 2024-01-01 Yeon J. Lee, Donald C. Rio
Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by loss of motor neurons. Human genetic studies have linked mutations in RNA-binding proteins as causative for this disease. The hnRNPA1 protein, a known pre-mRNA splicing factor, is mutated in some ALS patients. Here, two human cell models were generated to investigate how a mutation in the C-terminal low-complexity
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Reviewers, Volume 37 (2023) Genes Dev. (IF 10.5) Pub Date : 2023-11-01
The editors would like to thank the Editorial Board and the following scientists who reviewed papers and provided advice during 2023.
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A nonneural miRNA cluster mediates hearing via repression of two neural targets Genes Dev. (IF 10.5) Pub Date : 2023-11-01 Binglong Zhang, Hong Duan, Joshua Kavaler, Lu Wei, Daniel F. Eberl, Eric C. Lai
We show here that mir-279/996 are absolutely essential for development and function of Johnston's organ (JO), the primary proprioceptive and auditory organ in Drosophila. Their deletion results in highly aberrant cell fate determination, including loss of scolopale cells and ectopic neurons, and mutants are electrophysiologically deaf. In vivo activity sensors and mosaic analyses indicate that these
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The steroid hormone ADIOL promotes learning by reducing neural kynurenic acid levels Genes Dev. (IF 10.5) Pub Date : 2023-11-01 George A. Lemieux, Shinja Yoo, Lin Lin, Mihir Vohra, Kaveh Ashrafi
Reductions in brain kynurenic acid levels, a neuroinhibitory metabolite, improve cognitive function in diverse organisms. Thus, modulation of kynurenic acid levels is thought to have therapeutic potential in a range of brain disorders. Here we report that the steroid 5-androstene 3β, 17β-diol (ADIOL) reduces kynurenic acid levels and promotes associative learning in Caenorhabditis elegans. We identify
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AI-assisted proofreading of RNA splicing Genes Dev. (IF 10.5) Pub Date : 2023-11-01 Ángel Guerra-Moreno, Juan Valcárcel
RNA helicases orchestrate proofreading mechanisms that facilitate accurate intron removal from pre-mRNAs. How these activities are recruited to spliceosome/pre-mRNA complexes remains poorly understood. In this issue of Genes & Development, Zhang and colleagues (pp. 968–983) combine biochemical experiments with AI-based structure prediction methods to generate a model for the interaction between SF3B1
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LINE-1 retrotransposition and its deregulation in cancers: implications for therapeutic opportunities Genes Dev. (IF 10.5) Pub Date : 2023-11-01 Carlos Mendez-Dorantes, Kathleen H. Burns
Long interspersed element 1 (LINE-1) is the only protein-coding transposon that is active in humans. LINE-1 propagates in the genome using RNA intermediates via retrotransposition. This activity has resulted in LINE-1 sequences occupying approximately one-fifth of our genome. Although most copies of LINE-1 are immobile, ∼100 copies are retrotransposition-competent. Retrotransposition is normally limited
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Restrictor synergizes with Symplekin and PNUTS to terminate extragenic transcription Genes Dev. (IF 10.5) Pub Date : 2023-11-01 Marta Russo, Viviana Piccolo, Danilo Polizzese, Elena Prosperini, Carolina Borriero, Sara Polletti, Fabio Bedin, Mattia Marenda, Davide Michieletto, Gaurav Madappa Mandana, Simona Rodighiero, Alessandro Cuomo, Gioacchino Natoli
Transcription termination pathways mitigate the detrimental consequences of unscheduled promiscuous initiation occurring at hundreds of thousands of genomic cis-regulatory elements. The Restrictor complex, composed of the Pol II-interacting protein WDR82 and the RNA-binding protein ZC3H4, suppresses processive transcription at thousands of extragenic sites in mammalian genomes. Restrictor-driven termination
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Molecular basis for PHF7-mediated ubiquitination of histone H3 Genes Dev. (IF 10.5) Pub Date : 2023-11-01 Hyun Sik Lee, Injin Bang, Junghyun You, Tae-Kyeong Jeong, Chang Rok Kim, Minsang Hwang, Jong-Seo Kim, Sung Hee Baek, Ji-Joon Song, Hee-Jung Choi
The RING-type E3 ligase has been known for over two decades, yet its diverse modes of action are still the subject of active research. Plant homeodomain (PHD) finger protein 7 (PHF7) is a RING-type E3 ubiquitin ligase responsible for histone ubiquitination. PHF7 comprises three zinc finger domains: an extended PHD (ePHD), a RING domain, and a PHD. While the function of the RING domain is largely understood
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Characterization of the SF3B1–SUGP1 interface reveals how numerous cancer mutations cause mRNA missplicing Genes Dev. (IF 10.5) Pub Date : 2023-11-01 Jian Zhang, Jindou Xie, Ji Huang, Xiangyang Liu, Ruihong Xu, Jonas Tholen, Wojciech P. Galej, Liang Tong, James L. Manley, Zhaoqi Liu
The spliceosomal gene SF3B1 is frequently mutated in cancer. While it is known that SF3B1 hotspot mutations lead to loss of splicing factor SUGP1 from spliceosomes, the cancer-relevant SF3B1–SUGP1 interaction has not been characterized. To address this issue, we show by structural modeling that two regions flanking the SUGP1 G-patch make numerous contacts with the region of SF3B1 harboring hotspot
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ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy Genes Dev. (IF 10.5) Pub Date : 2023-10-01 Mingchao Wang, Xiaojuan Ran, Wendy Leung, Ajinkya Kawale, Sneha Saxena, Jian Ouyang, Parasvi S. Patel, Yuting Dong, Tao Yin, Jian Shu, Robert T. Manguso, Li Lan, Xiao-Fan Wang, Michael S. Lawrence, Lee Zou
The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do not respond to immunotherapy, highlighting the need for alternative approaches to target MMR-d cancer cells. Here, we show that inhibition of the ATR kinase preferentially kills MMR-d cancer cells. Mechanistically, ATR inhibitor (ATRi)
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Comprehensive mapping of cell fates in microsatellite unstable cancer cells supports dual targeting of WRN and ATR Genes Dev. (IF 10.5) Pub Date : 2023-10-01 Dali Zong, Natasha C. Koussa, James A. Cornwell, Ajith V. Pankajam, Michael J. Kruhlak, Nancy Wong, Raj Chari, Steven D. Cappell, André Nussenzweig
Addiction to the WRN helicase is a unique vulnerability of human cancers with high levels of microsatellite instability (MSI-H). However, while prolonged loss of WRN ultimately leads to cell death, little is known about how MSI-H cancers initially respond to acute loss of WRN—knowledge that would be helpful for informing clinical development of WRN targeting therapy, predicting possible resistance
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Reorganization of lamina-associated domains in early mouse embryos is regulated by RNA polymerase II activity Genes Dev. (IF 10.5) Pub Date : 2023-10-01 Mrinmoy Pal, Luis Altamirano-Pacheco, Tamas Schauer, Maria-Elena Torres-Padilla
Fertilization in mammals is accompanied by an intense period of chromatin remodeling and major changes in nuclear organization. How the earliest events in embryogenesis, including zygotic genome activation (ZGA) during maternal-to-zygotic transition, influence such remodeling remains unknown. Here, we have investigated the establishment of nuclear architecture, focusing on the remodeling of lamina-associated
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Imaging the binding of MECP2 to DNA Genes Dev. (IF 10.5) Pub Date : 2023-10-01 Anne E. West
Mutations in the methyl-DNA binding domain of MECP2 cause Rett syndrome; however, distinct mutations are associated with different severity of the disease. Live-cell imaging and single-molecule tracking are sensitive methods to quantify the DNA binding affinity and diffusion dynamics of nuclear proteins. In this issue of Genes & Development, Zhou and colleagues (pp. 883–900) used these imaging methods
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A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels Genes Dev. (IF 10.5) Pub Date : 2023-10-01 Jian Zhou, Claudia Cattoglio, Yingyao Shao, Harini P. Tirumala, Carlo Vetralla, Sameer S. Bajikar, Yan Li, Hu Chen, Qi Wang, Zhenyu Wu, Bing Tang, Mahla Zahabiyon, Aleksandar Bajic, Xiangling Meng, Jack J. Ferrie, Anel LaGrone, Ping Zhang, Jean J. Kim, Jianrong Tang, Zhandong Liu, Xavier Darzacq, Nathaniel Heintz, Robert Tjian, Huda Y. Zoghbi
Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation (c.353G>A, p.Gly118Glu [G118E]), which has never been seen before in MECP2, in a young boy who suffered from progressive
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MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival Genes Dev. (IF 10.5) Pub Date : 2023-10-01 Matthew Hurd, Jeffrey Pino, Kay Jang, Michael M. Allevato, Marina Vorontchikhina, Wataru Ichikawa, Yifan Zhao, Ryan Gates, Emily Villalpando, Michael J. Hamilton, Francesco Faiola, Songqin Pan, Yue Qi, Yu-Wen Hung, Thomas Girke, David Ann, Victoria Seewaldt, Ernest Martinez
The MYC oncogenic transcription factor is acetylated by the p300 and GCN5 histone acetyltransferases. The significance of MYC acetylation and the functions of specific acetylated lysine (AcK) residues have remained unclear. Here, we show that the major p300-acetylated K148(149) and K157(158) sites in human (or mouse) MYC and the main GCN5-acetylated K323 residue are reversibly acetylated in various
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Corrigendum: The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells Genes Dev. (IF 10.5) Pub Date : 2023-09-01 Adrian P. Bracken, Daniela Kleine-Kohlbrecher, Nikolaj Dietrich, Diego Pasini, Gaetano Gargiulo, Chantal Beekman, Kim Theilgaard-Mönch, Saverio Minucci, Bo T. Porse, Jean-Christophe Marine, Klaus H. Hansen, Kristian Helin
Genes & Development 21: 525–530 (2007)
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Folding makes an imprint Genes Dev. (IF 10.5) Pub Date : 2023-09-01 Stefan H. Stricker
Imprinted gene clusters are confined genomic regions containing genes with parent-of-origin-dependent transcriptional activity. In this issue of Genes & Development, Loftus and colleagues (pp. 829–843) made use of an insightful combination of descriptive approaches, genetic manipulations, and epigenome-editing approaches to show that differences in nuclear topology precede the onset of imprinted expression
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Allelic chromatin structure precedes imprinted expression of Kcnk9 during neurogenesis Genes Dev. (IF 10.5) Pub Date : 2023-09-01 Daniel Loftus, Bongmin Bae, Courtney M. Whilden, Amanda J. Whipple
Differences in chromatin state inherited from the parental gametes influence the regulation of maternal and paternal alleles in offspring. This phenomenon, known as genomic imprinting, results in genes preferentially transcribed from one parental allele. While local epigenetic factors such as DNA methylation are known to be important for the establishment of imprinted gene expression, less is known
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In vitro reconstitution of SARS-CoV-2 Nsp1-induced mRNA cleavage reveals the key roles of the N-terminal domain of Nsp1 and the RRM domain of eIF3g Genes Dev. (IF 10.5) Pub Date : 2023-09-01 Irina S. Abaeva, Yani Arhab, Anna Miścicka, Christopher U.T. Hellen, Tatyana V. Pestova
SARS CoV-2 nonstructural protein 1 (Nsp1) is the major pathogenesis factor that inhibits host translation using a dual strategy of impairing initiation and inducing endonucleolytic cleavage of cellular mRNAs. To investigate the mechanism of cleavage, we reconstituted it in vitro on β-globin, EMCV IRES, and CrPV IRES mRNAs that use unrelated initiation mechanisms. In all instances, cleavage required
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Mesenchymal stromal cells as conductors of adipose tissue remodeling Genes Dev. (IF 10.5) Pub Date : 2023-09-01 Jessica Cannavino, Rana K. Gupta
Adipose tissue exhibits a remarkable capacity to expand, contract, and remodel in response to changes in physiological and environmental conditions. Here, we describe recent advances in our understanding of how functionally distinct tissue-resident mesenchymal stromal cell subpopulations orchestrate several aspects of physiological and pathophysiological adipose tissue remodeling, with a particular
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Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer Genes Dev. (IF 10.5) Pub Date : 2023-09-01 Jincheng Han, Jiaqian Xu, Yonghong Liu, Shaoheng Liang, Kyle A. LaBella, Deepavali Chakravarti, Denise J. Spring, Yan Xia, Ronald A. DePinho
Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial antitumor activity followed by recurrence due to cancer cell-intrinsic and immune-mediated paracrine mechanisms. Here, we explored the potential role of cancer-associated fibroblasts (CAFs) in enabling KRAS* bypass and identified CAF-derived
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Distinct accessory roles of Arabidopsis VEL proteins in Polycomb silencing Genes Dev. (IF 10.5) Pub Date : 2023-09-01 Elsa Franco-Echevarría, Mathias Nielsen, Anna Schulten, Jitender Cheema, Tomos E. Morgan, Mariann Bienz, Caroline Dean
Polycomb repressive complex 2 (PRC2) mediates epigenetic silencing of target genes in animals and plants. In Arabidopsis, PRC2 is required for the cold-induced epigenetic silencing of the FLC floral repressor locus to align flowering with spring. During this process, PRC2 relies on VEL accessory factors, including the constitutively expressed VRN5 and the cold-induced VIN3. The VEL proteins are physically
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Uncovering a mammalian neural-specific poly(A) binding protein with unique properties Genes Dev. (IF 10.5) Pub Date : 2023-08-01 Sahil Sharma, Sam Kajjo, Zineb Harra, Benedeta Hasaj, Victoria Delisle, Debashish Ray, Rodrigo L. Gutierrez, Isabelle Carrier, Claudia Kleinman, Quaid Morris, Timothy R. Hughes, Roderick McInnes, Marc R. Fabian
The mRNA 3′ poly(A) tail plays a critical role in regulating both mRNA translation and turnover. It is bound by the cytoplasmic poly(A) binding protein (PABPC), an evolutionarily conserved protein that can interact with translation factors and mRNA decay machineries to regulate gene expression. Mammalian PABPC1, the prototypical PABPC, is expressed in most tissues and interacts with eukaryotic translation
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Advancing therapeutics using antibody-induced dimerization of receptor tyrosine phosphatases Genes Dev. (IF 10.5) Pub Date : 2023-08-01 Michel L. Tremblay
Receptor protein tyrosine phosphatases (RPTPs) are involved in a broad list of cellular, developmental, and physiological functions. Altering their expression leads to significant changes in protein phosphorylation linked to a growing list of human diseases, including cancers and neurological disorders. In this issue of Genes & Development, Qian and colleagues (pp. 743–759) present the identification
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Putting a finger on histidine methylation Genes Dev. (IF 10.5) Pub Date : 2023-08-01 Paul L. Boutz
Specialized enzymes add methyl groups to the nitrogens of the amino acid histidine, altering the chemical properties of its imidazole ring and, in turn, the function of the modified (poly)peptide. In this issue of Genes & Development, Shimazu and colleagues (pp. 724–742) make the remarkable discovery that CARNMT1 acts as a dual-specificity histidine methyltransferase, modifying both the small-molecule
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Transcription factor networks link B-lymphocyte development and malignant transformation in leukemia Genes Dev. (IF 10.5) Pub Date : 2023-08-01 Mikael Sigvardsson
Rapid advances in genomics have opened unprecedented possibilities to explore the mutational landscapes in malignant diseases, such as B-cell acute lymphoblastic leukemia (B-ALL). This disease is manifested as a severe defect in the production of normal blood cells due to the uncontrolled expansion of transformed B-lymphocyte progenitors in the bone marrow. Even though classical genetics identified
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Manipulating PTPRD function with ectodomain antibodies Genes Dev. (IF 10.5) Pub Date : 2023-08-01 Zhe Qian, Dongyan Song, Jonathan J. Ipsaro, Carmelita Bautista, Leemor Joshua-Tor, Johannes T.-H. Yeh, Nicholas K. Tonks
Protein tyrosine phosphatases (PTPs) are critical regulators of signal transduction but have yet to be exploited fully for drug development. Receptor protein tyrosine phosphatase δ (RPTPδ/PTPRD) has been shown to elicit tumor-promoting functions, including elevating SRC activity and promoting metastasis in certain cell contexts. Dimerization has been implicated in the inhibition of receptor protein
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Metabolic partitioning in the brain and its hijacking by glioblastoma Genes Dev. (IF 10.5) Pub Date : 2023-08-01 Jed de Ruiter Swain, Evdokia Michalopoulou, Evan K. Noch, Michael J. Lukey, Linda Van Aelst
The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of metabolic pathways between these cells, such as in the neuron–astrocyte glutamate–glutamine cycle. An emerging theme in glioblastoma (GBM) biology is that malignant cells integrate into or “hijack” brain metabolism, co-opting neurons
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Histidine N1-position-specific methyltransferase CARNMT1 targets C3H zinc finger proteins and modulates RNA metabolism Genes Dev. (IF 10.5) Pub Date : 2023-08-01 Tadahiro Shimazu, Rei Yoshimoto, Kaoru Kotoshiba, Takehiro Suzuki, Shogo Matoba, Michiko Hirose, Mai Akakabe, Yoshihiro Sohtome, Mikiko Sodeoka, Atsuo Ogura, Naoshi Dohmae, Yoichi Shinkai
Histidine (His) residues are methylated in various proteins, but their roles and regulation mechanisms remain unknown. Here, we show that carnosine N-methyltransferase 1 (CARNMT1), a known His methyltransferase of dipeptide carnosine (βAla-His), is a major His N1-position-specific methyltransferase. We found that 52 His sites in 20 proteins underwent CARNMT1-mediated methylation. The consensus methylation
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Target-directed microRNA degradation regulates developmental microRNA expression and embryonic growth in mammals Genes Dev. (IF 10.5) Pub Date : 2023-07-01 Benjamin T. Jones, Jaeil Han, He Zhang, Robert E. Hammer, Bret M. Evers, Dinesh Rakheja, Asha Acharya, Joshua T. Mendell
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that play critical roles in development and disease. Target-directed miRNA degradation (TDMD), a pathway in which miRNAs that bind to specialized targets with extensive complementarity are rapidly decayed, has emerged as a potent mechanism of controlling miRNA levels. Nevertheless, the biological role and scope of miRNA regulation
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Cell type-specific role of CBX2 and its disordered region in spermatogenesis Genes Dev. (IF 10.5) Pub Date : 2023-07-01 Jongmin J. Kim, Emma R. Steinson, Mei Sheng Lau, Dirk G. de Rooij, David C. Page, Robert E. Kingston
Polycomb group (PcG) proteins maintain the repressed state of lineage-inappropriate genes and are therefore essential for embryonic development and adult tissue homeostasis. One critical function of PcG complexes is modulating chromatin structure. Canonical Polycomb repressive complex 1 (cPRC1), particularly its component CBX2, can compact chromatin and phase-separate in vitro. These activities are
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RUNX1 is required in granulocyte–monocyte progenitors to attenuate inflammatory cytokine production by neutrophils Genes Dev. (IF 10.5) Pub Date : 2023-07-01 Alexandra U. Zezulin, Daniel Yen, Darwin Ye, Elizabeth D. Howell, Erica Bresciani, Jamie Diemer, Jian-gang Ren, Mohd Hafiz Ahmad, Lucio H. Castilla, Ivo P. Touw, Andy J. Minn, Wei Tong, P. Paul Liu, Kai Tan, Wenbao Yu, Nancy A. Speck
The transcription factor RUNX1 is mutated in familial platelet disorder with associated myeloid malignancy (FPDMM) and in sporadic myelodysplastic syndrome and leukemia. RUNX1 was shown to regulate inflammation in multiple cell types. Here we show that RUNX1 is required in granulocyte–monocyte progenitors (GMPs) to epigenetically repress two inflammatory signaling pathways in neutrophils: Toll-like
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Delineation of two multi-invasion-induced rearrangement pathways that differently affect genome stability Genes Dev. (IF 10.5) Pub Date : 2023-07-01 Diedre Reitz, Yasmina Djeghmoum, Ruth A. Watson, Pallavi Rajput, Juan Lucas Argueso, Wolf-Dietrich Heyer, Aurèle Piazza
Punctuated bursts of structural genomic variations (SVs) have been described in various organisms, but their etiology remains incompletely understood. Homologous recombination (HR) is a template-guided mechanism of repair of DNA double-strand breaks and stalled or collapsed replication forks. We recently identified a DNA break amplification and genome rearrangement pathway originating from the endonucleolytic
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Dynamic nucleosome remodeling mediated by YY1 underlies early mouse development Genes Dev. (IF 10.5) Pub Date : 2023-07-01 Mizuki Sakamoto, Shusaku Abe, Yuka Miki, Yusuke Miyanari, Hiroyuki Sasaki, Takashi Ishiuchi
Nucleosome positioning can alter the accessibility of DNA-binding proteins to their cognate DNA elements, and thus its precise control is essential for cell identity and function. Mammalian preimplantation embryos undergo temporal changes in gene expression and cell potency, suggesting the involvement of dynamic epigenetic control during this developmental phase. However, the dynamics of nucleosome
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CST–Polα/Primase: the second telomere maintenance machine Genes Dev. (IF 10.5) Pub Date : 2023-07-01 Sarah W. Cai, Titia de Lange
It has been known for decades that telomerase extends the 3′ end of linear eukaryotic chromosomes and dictates the telomeric repeat sequence based on the template in its RNA. However, telomerase does not mitigate sequence loss at the 5′ ends of chromosomes, which results from lagging strand DNA synthesis and nucleolytic processing. Therefore, a second enzyme is needed to keep telomeres intact: DNA
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Histone bivalency regulates the timing of cerebellar granule cell development Genes Dev. (IF 10.5) Pub Date : 2023-07-01 Kärt Mätlik, Eve-Ellen Govek, Matthew R. Paul, C. David Allis, Mary E. Hatten
Developing neurons undergo a progression of morphological and gene expression changes as they transition from neuronal progenitors to mature neurons. Here we used RNA-seq and H3K4me3 and H3K27me3 ChIP-seq to analyze how chromatin modifications control gene expression in a specific type of CNS neuron: the mouse cerebellar granule cell (GC). We found that in proliferating GC progenitors (GCPs), H3K4me3/H3K27me3
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Evolutionary conservation of the structure and function of meiotic Rec114−Mei4 and Mer2 complexes Genes Dev. (IF 10.5) Pub Date : 2023-06-01 Dima Daccache, Emma De Jonge, Pascaline Liloku, Karen Mechleb, Marita Haddad, Sam Corthaut, Yann G.-J. Sterckx, Alexander N. Volkov, Corentin Claeys Bouuaert
Meiosis-specific Rec114−Mei4 and Mer2 complexes are thought to enable Spo11-mediated DNA double-strand break (DSB) formation through a mechanism that involves DNA-dependent condensation. However, the structure, molecular properties, and evolutionary conservation of Rec114−Mei4 and Mer2 are unclear. Here, we present AlphaFold models of Rec114−Mei4 and Mer2 complexes supported by nuclear magnetic resonance
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Structure and DNA-bridging activity of the essential Rec114–Mei4 trimer interface Genes Dev. (IF 10.5) Pub Date : 2023-06-01 Kaixian Liu, Emily M. Grasso, Stephen Pu, Mengyang Zou, Shixin Liu, David Eliezer, Scott Keeney
The DNA double-strand breaks (DSBs) that initiate meiotic recombination are formed by an evolutionarily conserved suite of factors that includes Rec114 and Mei4 (RM), which regulate DSB formation both spatially and temporally. In vivo, these proteins form large immunostaining foci that are integrated with higher-order chromosome structures. In vitro, they form a 2:1 heterotrimeric complex that binds
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Translational regulation by uORFs and start codon selection stringency Genes Dev. (IF 10.5) Pub Date : 2023-06-01 Thomas E. Dever, Ivaylo P. Ivanov, Alan G. Hinnebusch
In addition to the main, protein-coding, open reading frame (mORF), many eukaryotic mRNAs contain upstream ORFs (uORFs) initiated at AUG or near-cognate codons residing 5′ of the mORF start site. Whereas translation of uORFs generally represses translation of the mORFs, a subset of uORFs serves as a nexus for regulating translation of the mORF. In this review, we summarize the mechanisms by which uORFs
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Differential use of the Nkx2.2 NK2 domain in developing pancreatic islets and neurons Genes Dev. (IF 10.5) Pub Date : 2023-06-01 Philip A. Seymour, Palle Serup
The homeodomain transcription factor (TF) Nkx2.2 governs crucial cell fate decisions in several developing organs, including the central nervous system (CNS), pancreas, and intestine. How Nkx2.2 regulates unique targets in these different systems to impact their individual transcriptional programs remains unclear. In this issue of Genes & Development Abarinov and colleagues (pp. 490–504) generated
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Nuclear mRNPs are compact particles packaged with a network of proteins promoting RNA–RNA interactions Genes Dev. (IF 10.5) Pub Date : 2023-06-01 Fabien Bonneau, Jérôme Basquin, Barbara Steigenberger, Tillman Schäfer, Ingmar B. Schäfer, Elena Conti
Messenger RNAs (mRNAs) are at the center of the central dogma of molecular biology. In eukaryotic cells, these long ribonucleic acid polymers do not exist as naked transcripts; rather, they associate with mRNA-binding proteins to form messenger ribonucleoprotein (mRNP) complexes. Recently, global proteomic and transcriptomic studies have provided comprehensive inventories of mRNP components. However
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Circadian mechanisms in adipose tissue bioenergetics and plasticity Genes Dev. (IF 10.5) Pub Date : 2023-06-01 Chelsea Hepler, Joseph Bass
The circadian clock plays an essential role in coordinating feeding and metabolic rhythms with the light/dark cycle. Disruption of clocks is associated with increased adiposity and metabolic disorders, whereas aligning feeding time with cell-autonomous rhythms in metabolism improves health. Here, we provide a comprehensive overview of recent literature in adipose tissue biology as well as our understanding
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Major β cell-specific functions of NKX2.2 are mediated via the NK2-specific domain Genes Dev. (IF 10.5) Pub Date : 2023-06-01 Vladimir Abarinov, Joshua A. Levine, Angela J. Churchill, Bryce Hopwood, Cailin S. Deiter, Michelle A. Guney, Kristen L. Wells, Jessica M. Schrunk, Yuchun Guo, Jennifer Hammelman, David K. Gifford, Mark A. Magnuson, Hynek Wichterle, Lori Sussel
The consolidation of unambiguous cell fate commitment relies on the ability of transcription factors (TFs) to exert tissue-specific regulation of complex genetic networks. However, the mechanisms by which TFs establish such precise control over gene expression have remained elusive—especially in instances in which a single TF operates in two or more discrete cellular systems. In this study, we demonstrate
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Corrigendum: Hierarchical reactivation of transcription during mitosis-to-G1 transition by Brn2 and Ascl1 in neural stem cells Genes Dev. (IF 10.5) Pub Date : 2023-05-01 Mario A.F. Soares, Diogo S. Soares, Vera Teixeira, Abeer Heskol, Raul Bardini Bressan, Steven M. Pollard, Raquel A. Oliveira, Diogo S. Castro
Genes & Development 35: 1020–1034 (2021)
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Designer genes courtesy of artificial intelligence Genes Dev. (IF 10.5) Pub Date : 2023-05-01 Alexander Hoffmann
The core promoter determines not only where gene transcription initiates but also the transcriptional activity in both basal and enhancer-induced conditions. Multiple short sequence elements within the core promoter have been identified in different species, but how they function together and to what extent they are truly species-specific has remained unclear. In this issue of Genes & Development,
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Long ant life span is maintained by a unique heat shock factor Genes Dev. (IF 10.5) Pub Date : 2023-05-01 Karl M. Glastad, Julian Roessler, Janko Gospocic, Roberto Bonasio, Shelley L. Berger
Eusocial insect reproductive females show strikingly longer life spans than nonreproductive female workers despite high genetic similarity. In the ant Harpegnathos saltator (Hsal), workers can transition to reproductive “gamergates,” acquiring a fivefold prolonged life span by mechanisms that are poorly understood. We found that gamergates have elevated expression of heat shock response (HSR) genes
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Germ cell-specific eIF4E1b regulates maternal mRNA translation to ensure zygotic genome activation Genes Dev. (IF 10.5) Pub Date : 2023-05-01 Guanghui Yang, Qiliang Xin, Iris Feng, Di Wu, Jurrien Dean
Translation of maternal mRNAs is detected before transcription of zygotic genes and is essential for mammalian embryo development. How certain maternal mRNAs are selected for translation instead of degradation and how this burst of translation affects zygotic genome activation remain unknown. Using gene-edited mice, we document that the oocyte-specific eukaryotic translation initiation factor 4E family
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Role of the proline-rich disordered domain of DROSHA in intronic microRNA processing Genes Dev. (IF 10.5) Pub Date : 2023-05-01 Soomin Son, Baekgyu Kim, Jihye Yang, V. Narry Kim
DROSHA serves as a gatekeeper of the microRNA (miRNA) pathway by processing primary transcripts (pri-miRNAs). While the functions of structured domains of DROSHA have been well documented, the contribution of N-terminal proline-rich disordered domain (PRD) remains elusive. Here we show that the PRD promotes the processing of miRNA hairpins located within introns. We identified a DROSHA isoform (p140)