Mitochondria are no longer viewed solely as ATP- or metabolite-generating organelles but as key regulators of cellular signaling that shape physiologic aging. Contrary to earlier theories linking aging to mitochondrial DNA mutations and oxidative damage, current evidence shows that these factors do not causally limit physiologic aging. Instead, an evolving literature links age-related loss of mitochondrial signaling and function to important physiologic changes of aging. Moreover, mild inhibition of mitochondrial respiratory function with drugs like metformin promote health span. These findings open new paths for pharmacologically reprogramming mitochondrial signaling to extend healthy aging.
{"title":"Mitochondria dysfunction: cause or consequence of physiologic aging?","authors":"G.R. Scott Budinger, Navdeep S. Chandel","doi":"10.1101/gad.353106.125","DOIUrl":"https://doi.org/10.1101/gad.353106.125","url":null,"abstract":"Mitochondria are no longer viewed solely as ATP- or metabolite-generating organelles but as key regulators of cellular signaling that shape physiologic aging. Contrary to earlier theories linking aging to mitochondrial DNA mutations and oxidative damage, current evidence shows that these factors do not causally limit physiologic aging. Instead, an evolving literature links age-related loss of mitochondrial signaling and function to important physiologic changes of aging. Moreover, mild inhibition of mitochondrial respiratory function with drugs like metformin promote health span. These findings open new paths for pharmacologically reprogramming mitochondrial signaling to extend healthy aging.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"6 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611026","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}
The past 40 years have witnessed significant progress in aging research. Although aging was once considered a stochastic process, it is now understood to be regulated by pathways and processes that can be dissected with modern cellular and molecular biology approaches. The aberrant accumulation of cells undergoing cellular senescence and an increase in chronic, sterile inflammation are two of those aging hallmarks. Here we discuss how these processes are connected and how the relationship between senescent cells and the immune system dictates the extent of inflammatory processes contributing to age-related dysfunction and disease.
{"title":"The interplay between senescence, inflammation, and the immune system","authors":"Jesús Gil","doi":"10.1101/gad.353125.125","DOIUrl":"https://doi.org/10.1101/gad.353125.125","url":null,"abstract":"The past 40 years have witnessed significant progress in aging research. Although aging was once considered a stochastic process, it is now understood to be regulated by pathways and processes that can be dissected with modern cellular and molecular biology approaches. The aberrant accumulation of cells undergoing cellular senescence and an increase in chronic, sterile inflammation are two of those aging hallmarks. Here we discuss how these processes are connected and how the relationship between senescent cells and the immune system dictates the extent of inflammatory processes contributing to age-related dysfunction and disease.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"11 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144611253","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}
Bérénice A. Benayoun, Alison Kochersberger, Jennifer L. Garrison
Ovarian aging is a critical yet understudied driver of systemic aging in female bodies, with profound implications for female health and longevity. Despite its significance, we still know little about ovarian aging and its systemic effects on aging trajectories. With new efforts over the past few years, interest in the field has been growing and there is momentum to address these questions. This review highlights the importance of leveraging modern tools and approaches to better understand ovarian aging and its impact on health span. Specifically, we believe it will be useful for both aging researchers looking to go into research on ovarian aging and reproductive researchers looking to adopt more modern toolkit. We focus on menopause—a key marker of ovarian aging—as a lens through which to examine the current state of the field, identify limitations in existing research, and outline goals for future progress. By emphasizing cutting-edge techniques and emerging models, we seek to illuminate new pathways for research that could lead to improved strategies for managing ovarian aging and enhancing overall female health.
{"title":"Studying ovarian aging and its health impacts: modern tools and approaches","authors":"Bérénice A. Benayoun, Alison Kochersberger, Jennifer L. Garrison","doi":"10.1101/gad.352732.125","DOIUrl":"https://doi.org/10.1101/gad.352732.125","url":null,"abstract":"Ovarian aging is a critical yet understudied driver of systemic aging in female bodies, with profound implications for female health and longevity. Despite its significance, we still know little about ovarian aging and its systemic effects on aging trajectories. With new efforts over the past few years, interest in the field has been growing and there is momentum to address these questions. This review highlights the importance of leveraging modern tools and approaches to better understand ovarian aging and its impact on health span. Specifically, we believe it will be useful for both aging researchers looking to go into research on ovarian aging and reproductive researchers looking to adopt more modern toolkit. We focus on menopause—a key marker of ovarian aging—as a lens through which to examine the current state of the field, identify limitations in existing research, and outline goals for future progress. By emphasizing cutting-edge techniques and emerging models, we seek to illuminate new pathways for research that could lead to improved strategies for managing ovarian aging and enhancing overall female health.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"22 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593971","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}
Shuying He, Pin Lyu, Marnie W. Skinner, Anthony Desotell, Brendan Foley, Chance M. McCaig, Wei Wang, Jiang Qian, Liang Tong, William F. Marzluff, Michael J. Matunis
Histone mRNAs are the only nonpolyadenylated mRNAs in eukaryotic cells and require specialized processing in the histone locus body (HLB), a nuclear body where essential processing factors, including the U7 snRNP, are concentrated. Recent studies have revealed that misregulation of histone pre-mRNA processing can lead to polyadenylation of histone mRNAs and disruption of histone protein homeostasis. Despite links to human disease, the factors contributing to polyadenylation of histone mRNAs and the mechanisms underlying HLB assembly and U7 snRNP biogenesis remain unclear. Here, we report novel functions of the small ubiquitin-related modifier 2 (SUMO2) in promoting histone pre-mRNA processing. Using a SUMO2 knockout osteosarcoma cell line, we identified a defect in 3′ end cleavage and a global increase in histone mRNA polyadenylation. Subsequent analysis of HLBs revealed increased dynamics and reduced levels of the U7 snRNP complex. By overexpressing the U7 snRNP-specific components Lsm11 and U7 snRNA, we rescued U7 snRNP levels and processing defects in SUMO2 knockout cells. Through analysis of Lsm11, we identified a SUMO-interacting motif in its N terminus required for efficient formation of U7 snRNP. Collectively, we demonstrated that SUMO2 promotes histone pre-mRNA 3′ end processing by stabilizing HLB interactions and facilitating U7 snRNP assembly.
{"title":"SUMO2 promotes histone pre-mRNA processing by stabilizing histone locus body interactions and facilitating U7 snRNP assembly","authors":"Shuying He, Pin Lyu, Marnie W. Skinner, Anthony Desotell, Brendan Foley, Chance M. McCaig, Wei Wang, Jiang Qian, Liang Tong, William F. Marzluff, Michael J. Matunis","doi":"10.1101/gad.352728.125","DOIUrl":"https://doi.org/10.1101/gad.352728.125","url":null,"abstract":"Histone mRNAs are the only nonpolyadenylated mRNAs in eukaryotic cells and require specialized processing in the histone locus body (HLB), a nuclear body where essential processing factors, including the U7 snRNP, are concentrated. Recent studies have revealed that misregulation of histone pre-mRNA processing can lead to polyadenylation of histone mRNAs and disruption of histone protein homeostasis. Despite links to human disease, the factors contributing to polyadenylation of histone mRNAs and the mechanisms underlying HLB assembly and U7 snRNP biogenesis remain unclear. Here, we report novel functions of the small ubiquitin-related modifier 2 (SUMO2) in promoting histone pre-mRNA processing. Using a SUMO2 knockout osteosarcoma cell line, we identified a defect in 3′ end cleavage and a global increase in histone mRNA polyadenylation. Subsequent analysis of HLBs revealed increased dynamics and reduced levels of the U7 snRNP complex. By overexpressing the U7 snRNP-specific components Lsm11 and U7 snRNA, we rescued U7 snRNP levels and processing defects in SUMO2 knockout cells. Through analysis of Lsm11, we identified a SUMO-interacting motif in its N terminus required for efficient formation of U7 snRNP. Collectively, we demonstrated that SUMO2 promotes histone pre-mRNA 3′ end processing by stabilizing HLB interactions and facilitating U7 snRNP assembly.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"93 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593973","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":"Corrigendum: FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity","authors":"Patrick C. Mahon, Kiichi Hirota, Gregg L. Semenza","doi":"10.1101/gad.352958.125","DOIUrl":"https://doi.org/10.1101/gad.352958.125","url":null,"abstract":"<strong>Genes & Development 15:</strong> 2675–2686 (2001)","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"25 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520507","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}
Differential mRNA expression is essential for driving cell type identity and cell fate transitions during tissue differentiation and organismal development. However, transcription kinetics are seemingly heterogeneous at a cell-to-cell level, occurring in a series of episodic bursts of nascent mRNA synthesis separated by refractory periods. This transcriptional bursting therefore affects both the speed and variability of developmental gene expression. Consequently, how transcription kinetics are modulated to control mRNA expression output remains an outstanding question in the field. This review examines recent literature on how these processes are modulated during differentiation and development, the theoretical models of transcription bursting, and the molecular mechanisms underlying transcription kinetics.
{"title":"Timing is everything: transcription bursting in development","authors":"Jee Min Kim, Daniel R. Larson","doi":"10.1101/gad.352465.124","DOIUrl":"https://doi.org/10.1101/gad.352465.124","url":null,"abstract":"Differential mRNA expression is essential for driving cell type identity and cell fate transitions during tissue differentiation and organismal development. However, transcription kinetics are seemingly heterogeneous at a cell-to-cell level, occurring in a series of episodic bursts of nascent mRNA synthesis separated by refractory periods. This transcriptional bursting therefore affects both the speed and variability of developmental gene expression. Consequently, how transcription kinetics are modulated to control mRNA expression output remains an outstanding question in the field. This review examines recent literature on how these processes are modulated during differentiation and development, the theoretical models of transcription bursting, and the molecular mechanisms underlying transcription kinetics.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"19 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520468","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}
Skyler Briggs, Ebba K. Blomqvist, Andres Cuellar, Derek Correa, James M. Burke
Oligoadenylate synthetases (OASs) are ancient proteins that play a critical role in combatting viruses in mammals. OASs are known to antagonize viral replication by binding viral dsRNA and synthesizing 2′–5′-oligo(A), which activates the antiviral endoribonuclease RNase L. Here, we investigate the antiviral activities of the human OAS isoforms (OAS1, OAS2, OAS3, and OASL) during West Nile virus (WNV) infection. We show that OAS3 is the primary OAS isoform required for activating RNase L. OAS3 condensation on dsRNA proximal to WNV replication organelles initiates RNase L activation. OAS3 contains three distinct dsRNA-binding domains that enhance its condensation on dsRNA. The potential for OAS3 to condense on dsRNA is modulated by dsRNA loads and OAS3 expression level, which can be constitutively expressed or induced by type I interferons. OAS1 and OAS2 do not frequently activate RNase L due to their weak potential to condense on dsRNA. However, they assemble into higher-order structures that aggregate full-length ssRNA viral genomes. OASL does not condense on dsRNA. Instead, OASL localizes to processing bodies, stress granules, and RNase L-induced bodies containing host and viral mRNA. These findings define the process of RNase L activation and elucidate the diversity of substrates and functions of human OAS proteins.
{"title":"Condensation of human OAS proteins initiates diverse antiviral activities in response to West Nile virus","authors":"Skyler Briggs, Ebba K. Blomqvist, Andres Cuellar, Derek Correa, James M. Burke","doi":"10.1101/gad.352725.125","DOIUrl":"https://doi.org/10.1101/gad.352725.125","url":null,"abstract":"Oligoadenylate synthetases (OASs) are ancient proteins that play a critical role in combatting viruses in mammals. OASs are known to antagonize viral replication by binding viral dsRNA and synthesizing 2′–5′-oligo(A), which activates the antiviral endoribonuclease RNase L. Here, we investigate the antiviral activities of the human OAS isoforms (OAS1, OAS2, OAS3, and OASL) during West Nile virus (WNV) infection. We show that OAS3 is the primary OAS isoform required for activating RNase L. OAS3 condensation on dsRNA proximal to WNV replication organelles initiates RNase L activation. OAS3 contains three distinct dsRNA-binding domains that enhance its condensation on dsRNA. The potential for OAS3 to condense on dsRNA is modulated by dsRNA loads and OAS3 expression level, which can be constitutively expressed or induced by type I interferons. OAS1 and OAS2 do not frequently activate RNase L due to their weak potential to condense on dsRNA. However, they assemble into higher-order structures that aggregate full-length ssRNA viral genomes. OASL does not condense on dsRNA. Instead, OASL localizes to processing bodies, stress granules, and RNase L-induced bodies containing host and viral mRNA. These findings define the process of RNase L activation and elucidate the diversity of substrates and functions of human OAS proteins.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"26 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520414","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}
Edel M. McCrea, Neoklis Makrides, Takako Tabata, Wencke Reineking, José G. Vilches-Moure, Mengxiong Wang, Julie S. Lake, Hannes Vogel, Brooke Howitt, Xin Zhang, Laura D. Attardi
The Hippo pathway regulates many physiological processes, including development, tumor suppression, and wound healing. One understudied Hippo pathway component is PTPN14, an evolutionarily conserved tyrosine phosphatase that inhibits YAP/TAZ. Although it is an established tumor suppressor, PTPN14's role in tissue homeostasis has remained unclear. We thus generated Ptpn14-deficient mice and found that only ∼60% of Ptpn14−/− mice survived postnatally, highlighting the importance of PTPN14 for viability while also enabling the discovery of PTPN14 physiological functions. Ptpn14−/− mice developed debilitating corneal lesions and the uterus defect hydrometra, as well as heart and kidney abnormalities. Ptpn14 deficiency precipitated an impaired injury response in the cornea and dysregulated YAP signaling in both the uterus and the cornea. Notably, these phenotypes were female-specific, revealing sexually dimorphic Hippo pathway function through PTPN14. Finally, analysis of human PTPN14 variants suggested that PTPN14's essential roles are conserved in humans, underscoring the importance of our insights for designing therapies to improve women's health.
{"title":"Analysis of knockout mice reveals critical female-specific roles for the Hippo pathway component PTPN14","authors":"Edel M. McCrea, Neoklis Makrides, Takako Tabata, Wencke Reineking, José G. Vilches-Moure, Mengxiong Wang, Julie S. Lake, Hannes Vogel, Brooke Howitt, Xin Zhang, Laura D. Attardi","doi":"10.1101/gad.352620.125","DOIUrl":"https://doi.org/10.1101/gad.352620.125","url":null,"abstract":"The Hippo pathway regulates many physiological processes, including development, tumor suppression, and wound healing. One understudied Hippo pathway component is PTPN14, an evolutionarily conserved tyrosine phosphatase that inhibits YAP/TAZ. Although it is an established tumor suppressor, PTPN14's role in tissue homeostasis has remained unclear. We thus generated <em>Ptpn14</em>-deficient mice and found that only ∼60% of <em>Ptpn14</em><sup>−<em>/</em>−</sup> mice survived postnatally, highlighting the importance of PTPN14 for viability while also enabling the discovery of PTPN14 physiological functions. <em>Ptpn14</em><sup>−<em>/</em>−</sup> mice developed debilitating corneal lesions and the uterus defect hydrometra, as well as heart and kidney abnormalities. <em>Ptpn14</em> deficiency precipitated an impaired injury response in the cornea and dysregulated YAP signaling in both the uterus and the cornea. Notably, these phenotypes were female-specific, revealing sexually dimorphic Hippo pathway function through PTPN14. Finally, analysis of human <em>PTPN14</em> variants suggested that PTPN14's essential roles are conserved in humans, underscoring the importance of our insights for designing therapies to improve women's health.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"15 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319846","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}
Agata Izabela Kalita, Eric Marois, Frank Rühle, Claudia Isabelle Keller Valsecchi
Malaria-transmitting mosquitoes are extremely sexually dimorphic in their anatomy and behavior. Sex-specific gene expression in Anopheles gambiae is well studied in adult stages, but its onset during embryogenesis, apart from sex determination factors like Yob, remains largely unknown. Here, we report a comprehensive single-embryo transcriptome atlas of A. gambiae males and females to understand the earliest stages of establishing the sex-specific expression networks. Our data set reveals embryonic RNA isoform diversity, including a global shift toward distal alternative polyadenylation (APA) event sites during the maternal-to-zygotic genome transition. Sex-biased gene expression and alternative splicing are limited during embryogenesis, with most sex-specific patterns emerging postembryonically. X-chromosome dosage compensation (DC) is established shortly after zygotic genome activation, concomitant with direct binding of the master regulator protein SOA to X-linked promoters. In contrast to known DC regulators in other species, we did not find evidence for early high-affinity sites or distance-dependent patterns in Anopheles. Instead, SOA binding and DC are dynamically specified on genes according to gene activity, where the most strongly expressed genes tend to show the strongest SOA binding. We propose that the Anopheles DC system represents an extreme case of a gene-by-gene regulatory mechanism that operates at the chromosome-wide level.
{"title":"Sex-specific transcriptome dynamics of Anopheles gambiae during embryonic development","authors":"Agata Izabela Kalita, Eric Marois, Frank Rühle, Claudia Isabelle Keller Valsecchi","doi":"10.1101/gad.352572.124","DOIUrl":"https://doi.org/10.1101/gad.352572.124","url":null,"abstract":"Malaria-transmitting mosquitoes are extremely sexually dimorphic in their anatomy and behavior. Sex-specific gene expression in <em>Anopheles gambiae</em> is well studied in adult stages, but its onset during embryogenesis, apart from sex determination factors like <em>Yob</em>, remains largely unknown. Here, we report a comprehensive single-embryo transcriptome atlas of <em>A. gambiae</em> males and females to understand the earliest stages of establishing the sex-specific expression networks. Our data set reveals embryonic RNA isoform diversity, including a global shift toward distal alternative polyadenylation (APA) event sites during the maternal-to-zygotic genome transition. Sex-biased gene expression and alternative splicing are limited during embryogenesis, with most sex-specific patterns emerging postembryonically. X-chromosome dosage compensation (DC) is established shortly after zygotic genome activation, concomitant with direct binding of the master regulator protein SOA to X-linked promoters. In contrast to known DC regulators in other species, we did not find evidence for early high-affinity sites or distance-dependent patterns in <em>Anopheles</em>. Instead, SOA binding and DC are dynamically specified on genes according to gene activity, where the most strongly expressed genes tend to show the strongest SOA binding. We propose that the <em>Anopheles</em> DC system represents an extreme case of a gene-by-gene regulatory mechanism that operates at the chromosome-wide level.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"147 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319876","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}
Gabriela Fort, Henry Arnold, Soledad A. Camolotto, Kayla O'Toole, Rushmeen Tariq, Anna Waters, Katherine Gillis, Eric L. Snyder
Lineage plasticity is critical for tumor progression and therapy resistance, but the molecular mechanisms underlying cell identity shifts in cancer remain poorly understood. In lung adenocarcinoma (LUAD), the loss of pulmonary lineage fidelity and acquisition of alternate identity programs converge on hybrid identity (hybrid ID) states, which are postulated to be key intermediates in LUAD evolution and are characterized by the coactivation of developmentally incompatible identity programs within individual cells. Here, we uncover a previously unrecognized role for the gastrointestinal transcriptional regulator HNF4α in driving tumor growth and hybrid ID states in LUAD. In LUAD cells expressing the lung lineage specifier NKX2-1, HNF4α induces a GI/liver-like state by directly binding and activating its canonical targets. HNF4α also disrupts NKX2-1 genomic localization and dampens pulmonary identity within hybrid ID LUAD. We show that this hybrid ID state is maintained by sustained RAS/MEK signaling. Inhibition of the RAS/MEK signaling cascade augments NKX2-1 chromatin binding at pulmonary-specific genes and induces drug resistance-associated pulmonary signatures. Finally, we demonstrate that HNF4α depletion sensitizes LUAD cells to KRASG12D inhibition. Collectively, our data show that coexpression of opposing lineage specifiers is a novel mechanism of identity dysregulation in LUAD that influences both tumor progression and response to targeted therapy.
{"title":"Opposing lineage specifiers induce a protumor hybrid identity state in lung adenocarcinoma","authors":"Gabriela Fort, Henry Arnold, Soledad A. Camolotto, Kayla O'Toole, Rushmeen Tariq, Anna Waters, Katherine Gillis, Eric L. Snyder","doi":"10.1101/gad.352742.125","DOIUrl":"https://doi.org/10.1101/gad.352742.125","url":null,"abstract":"Lineage plasticity is critical for tumor progression and therapy resistance, but the molecular mechanisms underlying cell identity shifts in cancer remain poorly understood. In lung adenocarcinoma (LUAD), the loss of pulmonary lineage fidelity and acquisition of alternate identity programs converge on hybrid identity (hybrid ID) states, which are postulated to be key intermediates in LUAD evolution and are characterized by the coactivation of developmentally incompatible identity programs within individual cells. Here, we uncover a previously unrecognized role for the gastrointestinal transcriptional regulator HNF4α in driving tumor growth and hybrid ID states in LUAD. In LUAD cells expressing the lung lineage specifier NKX2-1, HNF4α induces a GI/liver-like state by directly binding and activating its canonical targets. HNF4α also disrupts NKX2-1 genomic localization and dampens pulmonary identity within hybrid ID LUAD. We show that this hybrid ID state is maintained by sustained RAS/MEK signaling. Inhibition of the RAS/MEK signaling cascade augments NKX2-1 chromatin binding at pulmonary-specific genes and induces drug resistance-associated pulmonary signatures. Finally, we demonstrate that HNF4α depletion sensitizes LUAD cells to KRAS<sup>G12D</sup> inhibition. Collectively, our data show that coexpression of opposing lineage specifiers is a novel mechanism of identity dysregulation in LUAD that influences both tumor progression and response to targeted therapy.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"39 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278221","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}
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