{"title":"Classifying the molecular functions of transcription factors beyond activation and repression.","authors":"Jinhong Dong, Michael J Guertin","doi":"10.1101/gad.352340.124","DOIUrl":"https://doi.org/10.1101/gad.352340.124","url":null,"abstract":"<p><p>Notch signaling is a highly conserved pathway activated by dynamic cellular interactions that initiates a molecular cascade that ultimately drives changes in gene expression. The Notch transcriptional complex (NTC) regulates genes that influence development and homeostasis. In this issue of <i>Genes & Development</i>, Rogers and colleagues (doi:10.1101/gad.352108.124) leverage a rapid Notch activation system combined with molecular genomic profiling to reveal that the NTC regulates the release of paused RNA polymerase to activate direct target genes. They also highlight the role of the SWI/SNF chromatin remodeling complex in establishing and maintaining chromatin accessibility to potentiate the activation of NTC target genes.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590292","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}
Hirak Sarkar, Eunmi Lee, Sereno L Lopez-Darwin, Yibin Kang
{"title":"Deciphering normal and cancer stem cell niches by spatial transcriptomics: opportunities and challenges.","authors":"Hirak Sarkar, Eunmi Lee, Sereno L Lopez-Darwin, Yibin Kang","doi":"10.1101/gad.351956.124","DOIUrl":"https://doi.org/10.1101/gad.351956.124","url":null,"abstract":"<p><p>Cancer stem cells (CSCs) often exhibit stem-like attributes that depend on an intricate stemness-promoting cellular ecosystem within their niche. The interplay between CSCs and their niche has been implicated in tumor heterogeneity and therapeutic resistance. Normal stem cells (NSCs) and CSCs share stemness features and common microenvironmental components, displaying significant phenotypic and functional plasticity. Investigating these properties across diverse organs during normal development and tumorigenesis is of paramount research interest and translational potential. Advancements in next-generation sequencing (NGS), single-cell transcriptomics, and spatial transcriptomics have ushered in a new era in cancer research, providing high-resolution and comprehensive molecular maps of diseased tissues. Various spatial technologies, with their unique ability to measure the location and molecular profile of a cell within tissue, have enabled studies on intratumoral architecture and cellular cross-talk within the specific niches. Moreover, delineation of spatial patterns for niche-specific properties such as hypoxia, glucose deprivation, and other microenvironmental remodeling are revealed through multilevel spatial sequencing. This tremendous progress in technology has also been paired with the advent of computational tools to mitigate technology-specific bottlenecks. Here we discuss how different spatial technologies are used to identify NSCs and CSCs, as well as their associated niches. Additionally, by exploring related public data sets, we review the current challenges in characterizing such niches, which are often hindered by technological limitations, and the computational solutions used to address them.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575831","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}
Lee Davidson, Jérôme O. Rouvière, Rui Sousa-Luís, Takayuki Nojima, Nicholas J. Proudfoot, Torben Heick Jensen, Steven West
{"title":"DNA-directed termination of mammalian RNA polymerase II","authors":"Lee Davidson, Jérôme O. Rouvière, Rui Sousa-Luís, Takayuki Nojima, Nicholas J. Proudfoot, Torben Heick Jensen, Steven West","doi":"10.1101/gad.351978.124","DOIUrl":"https://doi.org/10.1101/gad.351978.124","url":null,"abstract":"The best-studied mechanism of eukaryotic RNA polymerase II (RNAPII) transcriptional termination involves polyadenylation site-directed cleavage of the nascent RNA. The RNAPII-associated cleavage product is then degraded by XRN2, dislodging RNAPII from the DNA template. In contrast, prokaryotic RNAP and eukaryotic RNAPIII often terminate directly at T-tracts in the coding DNA strand. Here, we demonstrate a similar and omnipresent capability for mammalian RNAPII. Importantly, this termination mechanism does not require upstream RNA cleavage. Accordingly, T-tract-dependent termination can take place when XRN2 cannot be engaged. We show that T-tracts can terminate snRNA transcription independently of RNA cleavage by the Integrator complex. Importantly, we found genome-wide termination at T-tracts in promoter-proximal regions but not within protein-coding gene bodies. XRN2-dependent termination dominates downstream from protein-coding genes, but the T-tract process is sometimes used. Overall, we demonstrate global DNA-directed attrition of RNAPII transcription, suggesting that RNAPs retain the potential to terminate over T-rich sequences throughout evolution.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574711","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}
Matthew R. Kudelka, Yonit Lavin, Siman Sun, Elaine Fuchs
{"title":"Molecular and cellular dynamics of squamous cell carcinomas across tissues","authors":"Matthew R. Kudelka, Yonit Lavin, Siman Sun, Elaine Fuchs","doi":"10.1101/gad.351990.124","DOIUrl":"https://doi.org/10.1101/gad.351990.124","url":null,"abstract":"Squamous cell carcinomas (SCCs), arising from the skin, head and neck, lungs, esophagus, and cervix, are collectively among the most common cancers and a frequent cause of cancer morbidity and mortality. Despite distinct stratified epithelial tissues of origin, converging evidence points toward shared biologic pathways across SCCs. With recent breakthroughs in molecular technologies have come novel SCC treatment paradigms, including immunotherapies and targeted therapy. This review compares commonalities and differences across SCCs from different anatomical sites, including risk factors and genetics, as well as cellular and molecular programs driving tumorigenesis. We review landmark discoveries of the “cancer stem cells” (CSCs) that initiate and propagate SCCs and their gene and translational regulation programs. This has led to an appreciation that interactions between CSCs and the immune system play key roles in invasion and therapeutic resistance. Here, we review the unifying principles of SCCs that have emerged from these exciting advances in our understanding of these epithelial cancers.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490397","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}
Hexiao Wang, Claudia Canasto-Chibuque, Jun Hyun Kim, Marcel Hohl, Christina Leslie, Jorge S. Reis-Filho, John H.J. Petrini
{"title":"Chronic interferon-stimulated gene transcription promotes oncogene-induced breast cancer","authors":"Hexiao Wang, Claudia Canasto-Chibuque, Jun Hyun Kim, Marcel Hohl, Christina Leslie, Jorge S. Reis-Filho, John H.J. Petrini","doi":"10.1101/gad.351455.123","DOIUrl":"https://doi.org/10.1101/gad.351455.123","url":null,"abstract":"The MRE11 complex (comprising MRE11, RAD50, and NBS1) is integral to the maintenance of genome stability. We previously showed that a hypomorphic <em>Mre11</em> mutant mouse strain (<em>Mre11</em><sup><em>ATLD1/ATLD1</em></sup>) was highly susceptible to oncogene-induced breast cancer. Here we used a mammary organoid system to examine which MRE11-dependent responses are tumor-suppressive. We found that <em>Mre11</em><sup><em>ATLD1/ATLD1</em></sup> organoids exhibited an elevated interferon-stimulated gene (ISG) signature and sustained changes in chromatin accessibility. This <em>Mre11</em><sup><em>ATLD1/ATLD1</em></sup> phenotype depended on DNA binding of a nuclear innate immune sensor, IFI205. Ablation of <em>Ifi205</em> in <em>Mre11</em><sup><em>ATLD1/ATLD1</em></sup> organoids restored baseline and oncogene-induced chromatin accessibility patterns to those observed in WT. Implantation of <em>Mre11</em><sup><em>ATLD1/ATLD1</em></sup> organoids and activation of the oncogene led to aggressive metastatic breast cancer. This outcome was reversed in implanted <em>Ifi205</em><sup>−/−</sup> <em>Mre11</em><sup><em>ATLD1/ATLD1</em></sup> organoids. These data reveal a connection between innate immune signaling and tumor development in the mammary epithelium. Given the abundance of aberrant DNA structures that arise in the context of genome instability syndromes, the data further suggest that cancer predisposition in those contexts may be partially attributable to chronic innate immune transcriptional programs.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490358","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":"Circadian de(regulation) in physiology: implications for disease and treatment","authors":"Leonardo Vinicius Monteiro de Assis, Achim Kramer","doi":"10.1101/gad.352180.124","DOIUrl":"https://doi.org/10.1101/gad.352180.124","url":null,"abstract":"Time plays a crucial role in the regulation of physiological processes. Without a temporal control system, animals would be unprepared for cyclic environmental changes, negatively impacting their survival. Experimental studies have demonstrated the essential role of the circadian system in the temporal coordination of physiological processes. Translating these findings to humans has been challenging. Increasing evidence suggests that modern lifestyle factors such as diet, sedentarism, light exposure, and social jet lag can stress the human circadian system, contributing to misalignment; i.e., loss of phase coherence across tissues. An increasing body of evidence supports the negative impact of circadian disruption on several human health parameters. This review aims to provide a comprehensive overview of how circadian disruption influences various physiological processes, its long-term health consequences, and its association with various diseases. To illustrate the relevant consequences of circadian disruption, we focused on describing the many physiological consequences faced by shift workers, a population known to experience high levels of circadian disruption. We also discuss the emerging field of circadian medicine, its founding principles, and its potential impact on human health.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":10.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448383","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}
Sarmistha Banerjee, Sulagna Sanyal, Suchita Hodawadekar, Sarah Naiyer, Nasreen Bano, Anupam Banerjee, Joshua Rhoades, Dawei Dong, David Allman, Michael L Atchison
{"title":"YY1 knockout in pro-B cells impairs lineage commitment, enabling unusual hematopoietic lineage plasticity.","authors":"Sarmistha Banerjee, Sulagna Sanyal, Suchita Hodawadekar, Sarah Naiyer, Nasreen Bano, Anupam Banerjee, Joshua Rhoades, Dawei Dong, David Allman, Michael L Atchison","doi":"10.1101/gad.351734.124","DOIUrl":"10.1101/gad.351734.124","url":null,"abstract":"<p><p>During B-cell development, cells progress through multiple developmental stages, with the pro-B-cell stage defining commitment to the B-cell lineage. YY1 is a ubiquitous transcription factor that is capable of both activation and repression functions. We found here that knockout of YY1 at the pro-B-cell stage eliminates B lineage commitment. YY1 knockout pro-B cells can generate T lineage cells in vitro using the OP9-DL4 feeder system and in vivo after injection into sublethally irradiated Rag1<sup>-/-</sup> mice. These T lineage-like cells lose their B lineage transcript profile and gain a T-cell lineage profile. Single-cell RNA-seq experiments showed that as YY1 knockout pro-B cells transition into T lineage cells in vitro, various cell clusters adopt transcript profiles representing a multiplicity of hematopoietic lineages, indicating unusual lineage plasticity. In addition, YY1 KO pro-B cells in vivo can give rise to other hematopoietic lineages in vivo. Evaluation of RNA-seq, scRNA-seq, ChIP-seq, and scATAC-seq data indicates that YY1 controls numerous chromatin-modifying proteins leading to increased accessibility of alternative lineage genes in YY1 knockout pro-B cells. Given the ubiquitous nature of YY1 and its dual activation and repression functions, YY1 may regulate commitment in multiple cell lineages.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371578","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":"The area postrema: a critical mediator of brain-body interactions.","authors":"Daniëlle van de Lisdonk, Bo Li","doi":"10.1101/gad.352276.124","DOIUrl":"10.1101/gad.352276.124","url":null,"abstract":"<p><p>The dorsal vagal complex contains three structures: the area postrema, the nucleus tractus solitarii, and the dorsal motor nucleus of the vagus. These structures are tightly linked, both anatomically and functionally, and have important yet distinct roles in not only conveying peripheral bodily signals to the rest of the brain but in the generation of behavioral and physiological responses. Reports on the new discoveries in these structures were highlights of the symposium. In this outlook, we focus on the roles of the area postrema in mediating brain-body interactions and its potential utility as a therapeutic target, especially in cancer cachexia.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371576","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":"Cancer neuroscience at the brain-body interface.","authors":"Jeremy C Borniger","doi":"10.1101/gad.352288.124","DOIUrl":"10.1101/gad.352288.124","url":null,"abstract":"<p><p>Our approaches toward understanding cancer have evolved beyond cell-intrinsic and local microenvironmental changes within the tumor to encompass how the cancer interfaces with the entire host organism. The nervous system is uniquely situated at the interface between the brain and body, constantly receiving and sending signals back and forth to maintain homeostasis and respond to salient stimuli. It is becoming clear that various cancers disrupt this dialog between the brain and body via both neuronal and humoral routes, leading to aberrant brain activity and accelerated disease. In this outlook, I discuss this view of cancer as a homeostatic challenge, emphasize cutting-edge work, and provide outstanding questions that need to be answered to move the field forward.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371568","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":"What a wonderful world!","authors":"Claire Magnon","doi":"10.1101/gad.352278.124","DOIUrl":"10.1101/gad.352278.124","url":null,"abstract":"<p><p>The world of cancer science is moving toward a paradigm shift in making connections with neuroscience. After decades of research on genetic instability and mutations or on the tumor microenvironment, emerging evidence suggests that a malignant tumor is able to hijack and use the brain and its network of peripheral and central neurons as disrupters of homeostasis in the body. Whole-body homeostasis requires brain-body circuits to maintain survival and health via the processes of interoception, immunoception, and nociception. It is now likely that cancer disturbs physiological brain-body communication in making bidirectional brain tumor connections.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371577","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}