Genes & development最新文献

{"title":"Regulatory circuits that build and sustain noninfectious granulomas.","authors":"Annika Ridky, Linda Zhou, Misha Rosenbach, Thomas H Leung","doi":"10.1101/gad.354047.126","DOIUrl":"10.1101/gad.354047.126","url":null,"abstract":"<p><p>Noninfectious granulomas organize immune cells into persistent tissue aggregates without an identifiable pathogen. Across diverse diseases, inflammation that should resolve instead persists, producing hallmark pathologic changes in tissue architecture that compromise organ function. Here, we synthesize recent studies to move beyond linear cytokine models and propose that granulomas persist through regulatory circuits linking immune cells, metabolism, and stroma. Maintenance reflects reinforcement among these local programs rather than a single inflammatory pathway. Comparisons across granulomatous diseases, including sarcoidosis, can distinguish disease-specific wiring from conserved maintenance programs. Defining these programs should identify strategies to dismantle established lesions.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929645","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}

{"title":"Sharp cell type boundaries emerge from coordinated morphogen signaling.","authors":"Ruiqi Li, Yiqun Jiang, Sarah Platt, Tianchi Xin, Shagun Lukkad, Sarah Van, Kevin A Peterson, Ryan Driskell, Jonathan Zhu, Hainan Lam, Eva-LaRue Barber, David H Wang, Chae Ho Lim, Makoto Mark Taketo, Yuval Kluger, Peggy Myung","doi":"10.1101/gad.353815.126","DOIUrl":"10.1101/gad.353815.126","url":null,"abstract":"<p><p>Classic models of the French flag problem depict sharp cell type boundaries emerging from threshold responses to morphogen gradients. How discrete cell type boundaries arise from morphogen signals that vary continuously across developing tissues remains incompletely understood. We use hair follicle dermal condensate (DC) formation to study a sharp developmental transition in which proliferative progenitors undergo cell cycle exit concurrent with molecular differentiation. Using genetic and genomic approaches, we show that Wnt and Hedgehog signaling coordinate separable cellular events during DC commitment. Elevated Wnt signaling promotes cell cycle exit through reduced chromatin binding of the Hedgehog mediator GLI3, while Hedgehog signaling induces differentiation genes in a Wnt-dependent manner and simultaneously elevates Wnt activity. When these responses coincide, differentiation and cell cycle exit occur together, limiting the duration and abundance of intermediate states and producing a sharp boundary. When they do not, intermediate states persist and expand, producing a graded boundary. Thus, a sharp boundary can emerge from a continuous transition that is compressed in time and space.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13564204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929662","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}

{"title":"Human MutLα activates methylpurine DNA glycosylase to induce alkylation damage cytotoxicity.","authors":"Mohamed E Ashour, Ellissa Krekeler, Monika Chandan Bhowmik, Holland Kantar, Ning Tsao, Carlos Herrera-Montávez, Miaw-Sheue Tsai, Manal Zaher, Lyudmila Y Kadyrova, Farid A Kadyrov, Roberto Galletto, Nima Mosammaparast","doi":"10.1101/gad.353661.126","DOIUrl":"10.1101/gad.353661.126","url":null,"abstract":"<p><p>Alkylation chemotherapy is commonly used against tumors such as glioblastoma, yet resistance often develops through downregulation of mismatch repair (MMR). Previous work has established that loss of MMR prevents the excision of the thymine-containing strand across <i>O</i> ⁶meG-T mismatches, thereby avoiding the futile repair cycle that ultimately leads to cell death. Here, we provide an alternative explanation to this prevailing mechanism of chemoresistance by MMR loss. We found that the MMR protein MutLα physically and functionally interacts with the base excision repair (BER) enzyme methylpurine DNA glycosylase (MPG), which processes common alkylation adducts, such as 7meG and 3meA. Biochemical reconstitution demonstrates that MutLα activates MPG glycosylase activity by promoting MPG substrate binding, and enhancing MPG release from the abasic site product, thereby facilitating enzyme turnover. This glycosylase stimulation requires ATP hydrolysis as well as the MLH1-interacting region on MPG. Both MutLα or its ability to interact with MPG promote the generation of alkylation-induced abasic sites in cells, which contribute to the cytotoxicity of methyl methanesulfonate (MMS), an S_N2 alkylating agent that does not produce <i>O</i> ⁶meG. Our results provide new insight into the mechanism of alkylation chemoresistance and uncover an unappreciated cross-talk between MMR and BER.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929668","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}

{"title":"A HUWE1 regulatory helix gates ASCL1 degradation through its C-terminal phospho-degron in small cell lung cancer.","authors":"Keita Masuzawa, Kevin D Dong, Calvin XiaoYang Hu, Ting Peng, Yoochan Myung, Shilpa Singh, Xinyue Li, Tianchu Wang, Cyrus Jin, Joao A Paulo, Ka Yang, Ernst W Schmid, Matthew A Booker, Yixiang Li, Deli Hong, Suzan Lazo, Michael Y Tolstorukov, John G Doench, Leslie Duplaquet, Katherine A Donovan, Sumaiya Iqbal, Eric S Fischer, Brian B Liau, Steven P Gygi, Matthew G Oser","doi":"10.1101/gad.353898.126","DOIUrl":"https://doi.org/10.1101/gad.353898.126","url":null,"abstract":"<p><p>Lineage-defining transcription factors are key oncogenic drivers but remain difficult to target pharmacologically due to the absence of ligandable pockets. The molecular rules governing substrate recognition by large HECT ubiquitin ligases also remain incompletely understood, limiting efforts to exploit these enzymes for targeted protein degradation. Here we combine genome-wide CRISPR knockout screening with base editor tiling screens at amino acid resolution, both coupled to an endogenous knock-in reporter of the SCLC lineage oncogenic transcription factor ASCL1, to systematically interrogate the mechanisms governing its degradation. These complementary screens unbiasedly identify the HECT ubiquitin ligase HUWE1 as the dominant regulator of ASCL1 stability in small cell lung cancer (SCLC) and resolve a conserved C-terminal phospho-degron centered on Ser207 and terminal Trp/Phe residues that are required for HUWE1 docking and ubiquitin-mediated degradation. Unexpectedly, base editor screening further uncovers a previously unrecognized regulatory module within HUWE1: a short negatively charged helix that functions as an autoinhibitory gate controlling access of phospho-degron substrates to HUWE1. Charge-flipping mutations within this regulatory helix relieve autoinhibition and accelerate degradation of multiple HUWE1 phospho-degron substrates, including ASCL1 and the canonical HUWE1 substrate DDIT4. Stabilization of ASCL1 through degron disruption paradoxically impairs SCLC proliferation, revealing that dynamic proteasome-coupled turnover is required for transcription factor function. Together, these findings reveal molecular rules governing HUWE1 phospho-degron recognition and identify a regulatory gate controlling substrate engagement. They also illustrate a generalizable strategy for resolving degradation mechanisms of undruggable transcription factors in their endogenous cellular context.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929597","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}

{"title":"Tales of destruction and repair: the changing view of MYC proteins in tumorigenesis.","authors":"Laura Baranello, Dimitrios Papadopoulos, Martin Eilers","doi":"10.1101/gad.353899.126","DOIUrl":"https://doi.org/10.1101/gad.353899.126","url":null,"abstract":"<p><p>MYC proteins are classically viewed as oncoproteins because they act as DNA-bound transcription factors that drive characteristic gene expression programs. Building on this view, recent work has shown that MYC proteins engage in multiple protein complexes that resolve transcription-associated stress and that they function as both DNA- and RNA-binding proteins. These findings suggest that, through these activities, MYC proteins enhance the stress resilience of proliferating cells and enable tumor cells to sustain nonphysiological, oncogenic gene expression programs.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148919371","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}

{"title":"MCM10 and RECQL4 have cooperative and redundant roles in activating the CMG helicase during the replication initiation.","authors":"Atabek Bektash, Xiaoxuan Zhu, Yuki Hatoyama, Atsushi Toyoda, Masato T Kanemaki","doi":"10.1101/gad.353714.126","DOIUrl":"https://doi.org/10.1101/gad.353714.126","url":null,"abstract":"<p><p>DNA replication initiation requires activation of the CMG helicase to establish the replisome. This process involves the extrusion of single-stranded DNA (ssDNA) from the central channel of MCM double hexamers, allowing the two CMG helicases to pass each other; however, the factors that mediate this process in human cells remain unclear. We show that degron-mediated depletion of either MCM10 or RECQL4 alone causes mild replication defects, whereas simultaneous depletion of both proteins severely impairs CMG activation. ChIP-seq analyses demonstrate that RECQL4 localizes to replication initiation zones (IZs) independently of MCM10, whereas MCM10 recruitment to IZs is enhanced upon RECQL4 depletion, consistent with partially redundant roles during CMG activation. Rescue experiments further indicate that RECQL4 cooperates with MCM10 through direct interaction, and that their ssDNA-binding activity underlies their functional overlap. We propose that MCM10 and RECQL4 act cooperatively and redundantly to promote CMG activation.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891494","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}

{"title":"Decoding anterior-posterior patterning cues into embryo-wide binary fate decisions through recruitment-mediated targeting.","authors":"Long Xiao, Yulin Cong, Huan Qi, Yuchuan Bai, Xuehua Ma, Zixin Zhou, Xiahe Huang, Yingchun Wang, Zhuo Du","doi":"10.1101/gad.353848.126","DOIUrl":"https://doi.org/10.1101/gad.353848.126","url":null,"abstract":"<p><p>Developmental pattern formation requires patterning cues to be converted into discrete, gene- and cell-specific regulatory outputs, but how this conversion is achieved remains unclear. We address this problem in <i>Caenorhabditis elegans</i> anterior-posterior patterning, where quantitatively asymmetric Wnt/β-catenin cues, namely anterior-enriched POP-1/TCF and posterior-enriched SYS-1/β-catenin, are decoded into binary, switch-like fate decisions. We show that these cues are resolved into embryo-wide binary regulatory outputs through ZIP-7/DBP, a transcription factor with stage-specific, lineage-wide posterior-exclusive expression that is essential for multiple posterior fate decisions. We define a model for this cue-to-decision decoding. At the <i>zip-7</i> promoter, the transcription factor ZIP-8/NFIL3, which begins to be expressed during mid-embryogenesis prior to ZIP-7 onset, provides an activating input while recruiting POP-1 and SYS-1. POP-1 restrains this activity anteriorly, whereas the POP-1-SYS-1 complex promotes it posteriorly, thereby generating a binary pattern of <i>zip-7</i> transcription. This recruitment-mediated promoter control couples Wnt/β-catenin cues to gene-specific transcriptional regulation and enables flexible spatiotemporal control of cue-dependent transcription. Genome-wide analyses further suggest that recruitment-mediated cotargeting may extend beyond <i>zip-7</i> and point to additional candidate factors with similar recruitment functions, supporting a scalable framework for decoding patterning cues into context-specific regulatory decisions.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873684","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}

{"title":"An antisense antidote to oncogenic poison exons.","authors":"René M Arvola, Guramrit Singh","doi":"10.1101/gad.353988.126","DOIUrl":"10.1101/gad.353988.126","url":null,"abstract":"<p><p>Splicing factors are frequently mutated in myeloid cancers, causing splicing aberrations that derail the expression of tumor suppressor genes. In SRSF2 mutated cancers, a key oncogenic splicing event is the inclusion of a \"poison\" exon that introduces an early stop codon in <i>EZH2</i> mRNA, causing its destabilization. In this issue of <i>Genes & Development</i>, Islam et al. (doi:10.1101/gad.353628.126) define how mutant SRSF2 binding to the poison exon mediates its inclusion and identify an antisense oligonucleotide that represses the exon to restore EZH2 function and rescues hematopoietic defects. Thus, targeting of poison exons, many of which show protumorigenic and antitumorigenic properties, is a promising new avenue to treat cancer.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1367-1369"},"PeriodicalIF":7.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13532538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700479","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}

{"title":"Machine learning analysis of the human initiator region reveals key features of different types of core promoters.","authors":"Torrey E Rhyne-Carrigg, Long Vo Ngoc, Claudia Medrano, Kassidy E Gillespie, James T Kadonaga","doi":"10.1101/gad.353623.125","DOIUrl":"10.1101/gad.353623.125","url":null,"abstract":"<p><p>The initiator (Inr) is the starting point for the transcription of many genes. Here, we generated highly predictive machine learning models of the human Inr region, and determined that the Inr is present in ∼60% of focused human promoters, identified a novel TATA-specific Inr, and detected the overlapping but functionally distinct TCT motif. Quantitative genome-wide analyses revealed a strict and synergistic interaction between the Inr and DPR, an inverse relationship between the TATA and DPR, a flexible and sometimes independent function of the TATA box in relation to the Inr, and different properties of the TCT motif in humans versus <i>Drosophila</i>.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1397-1407"},"PeriodicalIF":7.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13532657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648460","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}

{"title":"Adaptation of eukaryotic membrane homeostasis to species-specific cellular lipid landscapes.","authors":"Elisa Gomez-Gil, Paolo Guerra, Ying Gu, Sherman Foo, Benedicte Billard, Gabor Balogh, Maria Peter, Snezhana Oliferenko","doi":"10.1101/gad.353500.125","DOIUrl":"10.1101/gad.353500.125","url":null,"abstract":"<p><p>The physicochemical properties of biological membranes must be maintained within a range compatible with cellular physiology. In the face of external perturbations, membrane lipid homeostasis mechanisms sense and control membrane features. How such mechanisms evolve to function in organisms with different cellular lipid make-up is unknown. Here, we address this fundamental question by exploiting the natural divergence in membrane lipid composition between the related fission yeasts <i>Schizosaccharomyces pombe</i> and <i>Schizosaccharomyces japonicus</i> Using lipidomics and transcriptomics, we show that the activity of the membrane-bound transcriptional activator Mga2, which regulates the Δ-9 desaturase Ole1 expression, is set to sense distinct levels of membrane unsaturation in the two species. Through retroengineering and physiological experiments, we identified an evolutionary divergent but functionally constrained element within the juxtamembrane region of Mga2, which fine-tunes its performance to species-specific lipid composition. Our experiments indicate that high baseline expression of <i>ole1</i>, set by <i>cis</i>-regulatory elements in its upstream noncoding region, has redefined the dynamic range of Mga2 activation in <i>S. pombe</i>, supporting high lipidome unsaturation. Our work explores an \"experiment of nature\" to highlight the broad principles underlying the organization and evolution of membrane homeostasis, which should be applicable to other genetic networks supporting cellular homeostatic processes.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"1429-1447"},"PeriodicalIF":7.4,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13532661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684195","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}