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}
Carlos Alfonso-Gonzalez, Mengjin Shi, Sakshi Gorey, Sarah Holec, Judit Carrasco, Michael Rauer, Stylianos Tsagkris, Fernando Mateos, Valérie Hilgers
Circular RNAs (circRNAs) arise from back-splicing of precursor RNAs and accumulate in the nervous systems of animals, where they are thought to regulate gene expression and synaptic function. Here, we show that neuronal circRNA biosynthesis is mediated by the pan-neuronal RNA-binding protein ELAV. In Drosophila embryos, we characterized the circRNA landscape in normal and elav mutant neurons. We found that neuronal circRNAs are globally (>75%) depleted upon ELAV knockout, and induction of ELAV expression drives ectopic RNA circularization. In brain tissue, ELAV binds to pre-mRNA introns flanking putative circRNAs and decreases efficiency of linear splicing in favor of intron pairing at reverse complementary matches, inducing circularization. Together, our data demonstrate that ELAV directly modulates splicing decisions to generate the neuronal circRNA landscape.
{"title":"ELAV mediates circular RNA biogenesis in neurons","authors":"Carlos Alfonso-Gonzalez, Mengjin Shi, Sakshi Gorey, Sarah Holec, Judit Carrasco, Michael Rauer, Stylianos Tsagkris, Fernando Mateos, Valérie Hilgers","doi":"10.1101/gad.352670.125","DOIUrl":"https://doi.org/10.1101/gad.352670.125","url":null,"abstract":"Circular RNAs (circRNAs) arise from back-splicing of precursor RNAs and accumulate in the nervous systems of animals, where they are thought to regulate gene expression and synaptic function. Here, we show that neuronal circRNA biosynthesis is mediated by the pan-neuronal RNA-binding protein ELAV. In <em>Drosophila</em> embryos, we characterized the circRNA landscape in normal and <em>elav</em> mutant neurons. We found that neuronal circRNAs are globally (>75%) depleted upon ELAV knockout, and induction of ELAV expression drives ectopic RNA circularization. In brain tissue, ELAV binds to pre-mRNA introns flanking putative circRNAs and decreases efficiency of linear splicing in favor of intron pairing at reverse complementary matches, inducing circularization. Together, our data demonstrate that ELAV directly modulates splicing decisions to generate the neuronal circRNA landscape.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"2 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252319","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}
Liam C. Hunt, Beisi Xu, David Finkelstein, Yiping Fan, Patrick A. Carroll, Pei-Feng Cheng, Robert N. Eisenman, Fabio Demontis
Genes & Development 29: 2475–2489 (2015)
的基因,发展29:2475-2489 （2015）
{"title":"Corrigendum: The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling","authors":"Liam C. Hunt, Beisi Xu, David Finkelstein, Yiping Fan, Patrick A. Carroll, Pei-Feng Cheng, Robert N. Eisenman, Fabio Demontis","doi":"10.1101/gad.352856.125","DOIUrl":"https://doi.org/10.1101/gad.352856.125","url":null,"abstract":"<strong>Genes & Development 29:</strong> 2475–2489 (2015)","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"7 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193149","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}
Ian R. Powley, Alexander Kondrashov, Lucy A. Young, Helen C. Dobbyn, Kirsti Hill, Ian G. Cannell, Mark Stoneley, Yi-Wen Kong, Julia A. Cotes, Graeme C.M. Smith, Ron Wek, Christopher Hayes, Timothy W. Gant, Keith A. Spriggs, Martin Bushell, Anne E. Willis
Genes & Development 23: 1207–1220 (2009)
的基因,发展23:1207-1220 （2009）
{"title":"Retraction: Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes","authors":"Ian R. Powley, Alexander Kondrashov, Lucy A. Young, Helen C. Dobbyn, Kirsti Hill, Ian G. Cannell, Mark Stoneley, Yi-Wen Kong, Julia A. Cotes, Graeme C.M. Smith, Ron Wek, Christopher Hayes, Timothy W. Gant, Keith A. Spriggs, Martin Bushell, Anne E. Willis","doi":"10.1101/gad.352836.125","DOIUrl":"https://doi.org/10.1101/gad.352836.125","url":null,"abstract":"<strong>Genes & Development 23:</strong> 1207–1220 (2009)","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"51 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193119","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}
Hedda A. Meijer, Adam Hetherington, Sara J. Johnson, Rosie L. Gallagher, Izzah N. Hussein, Yuqi Weng, Jess M. Rae, Tomas E.J.C. Noordzij, Margarita Kalamara, Thomas J. Macartney, Lindsay Davidson, David M.A. Martin, Marek Gierlinski, Paul Davies, Katharina F. Sonnen, Philip J. Murray, J. Kim Dale
The segmentation clock is a molecular oscillator that regulates the timing of somite formation in the developing vertebrate embryo. NOTCH signaling is one of the key pathways required for proper functioning of the segmentation clock. Aberrant NOTCH signaling results in developmental abnormalities such as congenital scoliosis as well as diseases such as T-cell acute lymphoblastic lymphoma (T-ALL). In this study, we analyzed the effects of a mutation detected in T-ALL patients on somitogenesis using human iPSC-derived PSM cells and somitoids. Mutation of NOTCH1 serine 2513 into alanine compromises the interaction of Notch intracellular domain (NICD) with the F-box protein FBXW7 and consequently increases NICD stability and NICD levels in PSM cells. Moreover, the mutation impairs several aspects of clock gene oscillations such as signal intensity, periodicity, directionality of the oscillations, and the ability to sustain oscillations. Furthermore, it restricts the ability of somitoids to polarize, elongate, and form paired segments. The data suggest a mechanism by which post-translational modification of a key segmentation clock component plays a crucial role in vertebrate axis segmentation.
{"title":"NOTCH1 S2513 is critical for the regulation of NICD levels impacting the segmentation clock in hiPSC-derived PSM cells and somitoids","authors":"Hedda A. Meijer, Adam Hetherington, Sara J. Johnson, Rosie L. Gallagher, Izzah N. Hussein, Yuqi Weng, Jess M. Rae, Tomas E.J.C. Noordzij, Margarita Kalamara, Thomas J. Macartney, Lindsay Davidson, David M.A. Martin, Marek Gierlinski, Paul Davies, Katharina F. Sonnen, Philip J. Murray, J. Kim Dale","doi":"10.1101/gad.352909.125","DOIUrl":"https://doi.org/10.1101/gad.352909.125","url":null,"abstract":"The segmentation clock is a molecular oscillator that regulates the timing of somite formation in the developing vertebrate embryo. NOTCH signaling is one of the key pathways required for proper functioning of the segmentation clock. Aberrant NOTCH signaling results in developmental abnormalities such as congenital scoliosis as well as diseases such as T-cell acute lymphoblastic lymphoma (T-ALL). In this study, we analyzed the effects of a mutation detected in T-ALL patients on somitogenesis using human iPSC-derived PSM cells and somitoids. Mutation of NOTCH1 serine 2513 into alanine compromises the interaction of Notch intracellular domain (NICD) with the F-box protein FBXW7 and consequently increases NICD stability and NICD levels in PSM cells. Moreover, the mutation impairs several aspects of clock gene oscillations such as signal intensity, periodicity, directionality of the oscillations, and the ability to sustain oscillations. Furthermore, it restricts the ability of somitoids to polarize, elongate, and form paired segments. The data suggest a mechanism by which post-translational modification of a key segmentation clock component plays a crucial role in vertebrate axis segmentation.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"57 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176601","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}
Inés Fernández Maestre, Alexander S. Harris, Corina Amor
The rising global demographic aging and the subsequent increase in the prevalence of age-related diseases highlight the need to understand aging biology. A key player in organismal aging is the immune system, which has broad systemic effects. On the one hand, immune aging involves the decline of hematopoietic stem cells and significant alterations in the functionality and composition of both innate and adaptive immunity. On the other hand, the aged immune system contributes to chronic inflammation and disrupted tissue homeostasis, thereby driving systemic aging processes. In this review, we examine the close interaction between aging and the immune system and discuss emerging therapeutic strategies aimed at modulating immune function to mitigate age-related pathologies.
{"title":"Aging and immunity: the age-old tango","authors":"Inés Fernández Maestre, Alexander S. Harris, Corina Amor","doi":"10.1101/gad.352644.125","DOIUrl":"https://doi.org/10.1101/gad.352644.125","url":null,"abstract":"The rising global demographic aging and the subsequent increase in the prevalence of age-related diseases highlight the need to understand aging biology. A key player in organismal aging is the immune system, which has broad systemic effects. On the one hand, immune aging involves the decline of hematopoietic stem cells and significant alterations in the functionality and composition of both innate and adaptive immunity. On the other hand, the aged immune system contributes to chronic inflammation and disrupted tissue homeostasis, thereby driving systemic aging processes. In this review, we examine the close interaction between aging and the immune system and discuss emerging therapeutic strategies aimed at modulating immune function to mitigate age-related pathologies.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"1 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164776","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}
Iain Williamson, Katy A. Graham, Matthew Woolf, Hannes Becher, Robert E. Hill, Wendy A. Bickmore, Laura A. Lettice
Mammalian enhancers can regulate genes over large genomic distances, often skipping over other genes. Despite this, precise developmental regulation suggests that mechanisms exist to ensure enhancers only activate their correct targets. Sculpting of three-dimensional chromosome organization through cohesin-dependent loop extrusion is thought to be important for facilitating and constraining enhancer action. The boundaries of topologically associating domains (TADs) are thought to prevent enhancers acting on genes in adjacent TADs. However, there are examples where enhancers appear to act across TAD boundaries, but it has remained unclear whether a single enhancer can simultaneously activate genes in different TADs. Here we show that some Shh enhancers can activate transcription concurrently not only at Shh but also at Mnx1 located in an adjacent TAD. This occurs in the context of a chromatin conformation maintaining genes and enhancers in close proximity and is influenced by cohesin. To our knowledge, this is the first report of two endogenous mammalian genes transcribed concurrently under the control of the same enhancer and across a TAD boundary. These findings have implications for understanding the design rules of gene regulatory landscapes and are consistent with a transcription cluster model of enhancer–promoter communication.
{"title":"Bystander activation across a TAD boundary supports a cohesin-dependent transcription cluster model for enhancer function","authors":"Iain Williamson, Katy A. Graham, Matthew Woolf, Hannes Becher, Robert E. Hill, Wendy A. Bickmore, Laura A. Lettice","doi":"10.1101/gad.352648.125","DOIUrl":"https://doi.org/10.1101/gad.352648.125","url":null,"abstract":"Mammalian enhancers can regulate genes over large genomic distances, often skipping over other genes. Despite this, precise developmental regulation suggests that mechanisms exist to ensure enhancers only activate their correct targets. Sculpting of three-dimensional chromosome organization through cohesin-dependent loop extrusion is thought to be important for facilitating and constraining enhancer action. The boundaries of topologically associating domains (TADs) are thought to prevent enhancers acting on genes in adjacent TADs. However, there are examples where enhancers appear to act across TAD boundaries, but it has remained unclear whether a single enhancer can simultaneously activate genes in different TADs. Here we show that some Shh enhancers can activate transcription concurrently not only at <em>Shh</em> but also at <em>Mnx1</em> located in an adjacent TAD. This occurs in the context of a chromatin conformation maintaining genes and enhancers in close proximity and is influenced by cohesin. To our knowledge, this is the first report of two endogenous mammalian genes transcribed concurrently under the control of the same enhancer and across a TAD boundary. These findings have implications for understanding the design rules of gene regulatory landscapes and are consistent with a transcription cluster model of enhancer–promoter communication.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"19 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164775","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}
Luuli N. Tran, Ashwini Shinde, Kristen H. Schuster, Aiman Sabaawy, Emily Dale, Madalynn J. Welch, Trevor J. Isner, Sylvia A. Nunez, Fernando García-Moreno, Charles G. Sagerström, Bruce H. Appel, Santos J. Franco
The remarkable cell diversity of multicellular organisms relies on the ability of multipotent progenitor cells to generate distinct cell types at the right times and locations during embryogenesis. A key question is how progenitors establish competence to respond to the different environmental signals required to produce specific cell types at critical developmental time points. We addressed this in the mouse developing forebrain, where neural progenitor cells must switch from producing neurons to making oligodendrocytes in response to increased Sonic hedgehog (SHH) signaling during late embryogenesis. We show that progenitor responses to SHH are regulated by Notch signaling, thus permitting proper timing of the neuron–oligodendrocyte switch. Notch activity epigenetically primes genes associated with the oligodendrocyte lineage and SHH pathway, enabling amplified transcriptional responses to endogenous SHH and robust oligodendrogenesis. These results reveal a critical role for Notch in facilitating progenitor competence states and influencing cell fate transitions at the epigenetic level.
{"title":"Epigenetic priming of neural progenitors by Notch enhances Sonic hedgehog signaling and establishes gliogenic competence","authors":"Luuli N. Tran, Ashwini Shinde, Kristen H. Schuster, Aiman Sabaawy, Emily Dale, Madalynn J. Welch, Trevor J. Isner, Sylvia A. Nunez, Fernando García-Moreno, Charles G. Sagerström, Bruce H. Appel, Santos J. Franco","doi":"10.1101/gad.352555.124","DOIUrl":"https://doi.org/10.1101/gad.352555.124","url":null,"abstract":"The remarkable cell diversity of multicellular organisms relies on the ability of multipotent progenitor cells to generate distinct cell types at the right times and locations during embryogenesis. A key question is how progenitors establish competence to respond to the different environmental signals required to produce specific cell types at critical developmental time points. We addressed this in the mouse developing forebrain, where neural progenitor cells must switch from producing neurons to making oligodendrocytes in response to increased Sonic hedgehog (SHH) signaling during late embryogenesis. We show that progenitor responses to SHH are regulated by Notch signaling, thus permitting proper timing of the neuron–oligodendrocyte switch. Notch activity epigenetically primes genes associated with the oligodendrocyte lineage and SHH pathway, enabling amplified transcriptional responses to endogenous SHH and robust oligodendrogenesis. These results reveal a critical role for Notch in facilitating progenitor competence states and influencing cell fate transitions at the epigenetic level.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"133 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123067","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}
Claudia A. Mimoso, Hanneke Vlaming, Nathalie P. de Wagenaar, Allison P. Siegenfeld, Karen Adelman
The eukaryotic genome is broadly transcribed by RNA polymerase II (RNAPII) to produce protein-coding messenger RNAs (mRNAs) and a repertoire of noncoding RNAs (ncRNAs). Although RNAPII is very processive during mRNA transcription, it terminates rapidly during synthesis of many ncRNAs, particularly those that arise opportunistically from accessible chromatin at gene promoters or enhancers. The divergent fates of mRNA versus ncRNA species raise many questions about how RNAPII and associated machineries discriminate functional from spurious transcription. Restrictor, comprised of the RNA binding protein ZC3H4 and RNAPII-interacting protein WDR82, has been implicated in restraining the expression of ncRNAs. However, the determinants of Restrictor specificity and the mechanism of transcription suppression remain unclear. Here, we investigate Restrictor using unbiased sequence screens and rapid protein degradation followed by nascent RNA sequencing. We found that Restrictor promiscuously suppresses early elongation by RNAPII, but this activity is blocked at most mRNAs by the presence of a 5′ splice site. Consequently, Restrictor is a critical determinant of transcription directionality at divergent promoters and prevents transcriptional interference. Mechanistically, we show that rather than terminating RNAPII directly, Restrictor acts by reducing the rate of transcription elongation, rendering RNAPII susceptible to early termination by other machineries.
{"title":"Restrictor slows RNAPII elongation to promote termination at noncoding RNA loci","authors":"Claudia A. Mimoso, Hanneke Vlaming, Nathalie P. de Wagenaar, Allison P. Siegenfeld, Karen Adelman","doi":"10.1101/gad.352654.125","DOIUrl":"https://doi.org/10.1101/gad.352654.125","url":null,"abstract":"The eukaryotic genome is broadly transcribed by RNA polymerase II (RNAPII) to produce protein-coding messenger RNAs (mRNAs) and a repertoire of noncoding RNAs (ncRNAs). Although RNAPII is very processive during mRNA transcription, it terminates rapidly during synthesis of many ncRNAs, particularly those that arise opportunistically from accessible chromatin at gene promoters or enhancers. The divergent fates of mRNA versus ncRNA species raise many questions about how RNAPII and associated machineries discriminate functional from spurious transcription. Restrictor, comprised of the RNA binding protein ZC3H4 and RNAPII-interacting protein WDR82, has been implicated in restraining the expression of ncRNAs. However, the determinants of Restrictor specificity and the mechanism of transcription suppression remain unclear. Here, we investigate Restrictor using unbiased sequence screens and rapid protein degradation followed by nascent RNA sequencing. We found that Restrictor promiscuously suppresses early elongation by RNAPII, but this activity is blocked at most mRNAs by the presence of a 5′ splice site. Consequently, Restrictor is a critical determinant of transcription directionality at divergent promoters and prevents transcriptional interference. Mechanistically, we show that rather than terminating RNAPII directly, Restrictor acts by reducing the rate of transcription elongation, rendering RNAPII susceptible to early termination by other machineries.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"55 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104615","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 adipose-derived hormone leptin signals the adequacy of body triglyceride stores to specialized leptin receptor (LepRb)-containing cells, which modulate physiology and behavior appropriately for the status of energy reserves. Decreased leptin action initiates a program that restrains a host of energy-intensive processes, promotes food seeking and consumption, and supports the continued availability of glucose and other metabolic fuels in the face of diminished fat stores. In addition to activating the STAT3-dependent transcriptional regulation that mediates most leptin action in vivo, LepRb mediates some leptin effects via a poorly understood second intracellular signaling pathway. Leptin also activates feedback pathways that restrain LepRb signaling in the face of high leptin, as in obesity. Leptin mediates most of its metabolic effects via multiple populations of Lepr-expressing hypothalamic neurons, each of which controls different aspects of leptin action. Although most of these neuron populations contribute only modestly to the control of food intake and body weight by leptin, Glp1r-expressing Lepr neurons inhibit Agrp neurons and strongly suppress feeding and body weight. Going forward, it will be important to define the potentially distinct intracellular responses to leptin for individual Lepr neuron populations, along with the cell type-specific roles for these responses in the physiologic effects of leptin.
{"title":"Molecular mechanisms and neural mediators of leptin action","authors":"Cagri Bodur, Allison Duensing, Martin G. Myers","doi":"10.1101/gad.352550.124","DOIUrl":"https://doi.org/10.1101/gad.352550.124","url":null,"abstract":"The adipose-derived hormone leptin signals the adequacy of body triglyceride stores to specialized leptin receptor (LepRb)-containing cells, which modulate physiology and behavior appropriately for the status of energy reserves. Decreased leptin action initiates a program that restrains a host of energy-intensive processes, promotes food seeking and consumption, and supports the continued availability of glucose and other metabolic fuels in the face of diminished fat stores. In addition to activating the STAT3-dependent transcriptional regulation that mediates most leptin action in vivo, LepRb mediates some leptin effects via a poorly understood second intracellular signaling pathway. Leptin also activates feedback pathways that restrain LepRb signaling in the face of high leptin, as in obesity. Leptin mediates most of its metabolic effects via multiple populations of <em>Lepr</em>-expressing hypothalamic neurons, each of which controls different aspects of leptin action. Although most of these neuron populations contribute only modestly to the control of food intake and body weight by leptin, <em>Glp1r</em>-expressing <em>Lepr</em> neurons inhibit <em>Agrp</em> neurons and strongly suppress feeding and body weight. Going forward, it will be important to define the potentially distinct intracellular responses to leptin for individual <em>Lepr</em> neuron populations, along with the cell type-specific roles for these responses in the physiologic effects of leptin.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"2 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144104628","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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