Genes & development最新文献_第5页

The Rbfox1/LASR complex controls alternative pre-mRNA splicing by recognition of multipart RNA regulatory modules Rbfox1/LASR复合体通过识别多部分RNA调控模块来控制备选的pre-mRNA剪接

IF 10.5 1区生物学

Genes & development Pub Date : 2025-01-29 DOI: 10.1101/gad.352105.124

Parham Peyda, Chia-Ho Lin, Kelechi Onwuzurike, Douglas L. Black

{"title":"The Rbfox1/LASR complex controls alternative pre-mRNA splicing by recognition of multipart RNA regulatory modules","authors":"Parham Peyda, Chia-Ho Lin, Kelechi Onwuzurike, Douglas L. Black","doi":"10.1101/gad.352105.124","DOIUrl":"https://doi.org/10.1101/gad.352105.124","url":null,"abstract":"The Rbfox proteins regulate alternative pre-mRNA splicing by binding to the RNA element GCAUG. In the nucleus, most of Rbfox is bound to the large assembly of splicing regulators (LASR), a complex of RNA-binding proteins that recognize additional RNA motifs. However, it remains unclear how the different subunits of the Rbfox/LASR complex act together to bind RNA and regulate splicing. We used a nuclease protection assay to map the transcriptome-wide footprints of Rbfox1/LASR on nascent cellular RNA. In addition to GCAUG, Rbfox1/LASR binds RNA motifs for LASR subunits hnRNPs M, H/F, and C and Matrin3. These elements are often arranged in tandem, forming multipart modules of RNA motifs. To distinguish contact sites of Rbfox1 from the LASR subunits, we analyzed a mutant Rbfox1(F125A) that has lost RNA binding but remains associated with LASR. Rbfox1(F125A)/LASR complexes no longer interact with GCAUG but retain binding to RNA elements for LASR. Splicing analyses reveal that in addition to activating exons through adjacent GCAUG elements, Rbfox can also stimulate exons near binding sites for LASR subunits. Minigene experiments demonstrate that these diverse elements produce a combined regulatory effect on a target exon. These findings illuminate how a complex of RNA-binding proteins can decode combinatorial splicing regulatory signals by recognizing groups of tandem RNA elements.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"207 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056332","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}

引用次数: 0

Histone bivalency in CNS development 组蛋白二价在中枢神经系统发育中的作用

IF 10.5 1区生物学

Genes & development Pub Date : 2025-01-29 DOI: 10.1101/gad.352306.124

Kärt Mätlik, Eve-Ellen Govek, Mary E. Hatten

引用次数: 0

IF 10.5 1区生物学

Genes & development Pub Date : 2025-01-27 DOI: 10.1101/gad.352235.124

Yike Huang, Marjon J.A.M. Verstegen, Sjoerd J.D. Tjalsma, Peter H.L. Krijger, Kavvya Gupta, Minhee Park, Alistair Boettiger, Wouter de Laat

{"title":"Two unrelated distal genes activated by a shared enhancer benefit from localizing inside the same small topological domain","authors":"Yike Huang, Marjon J.A.M. Verstegen, Sjoerd J.D. Tjalsma, Peter H.L. Krijger, Kavvya Gupta, Minhee Park, Alistair Boettiger, Wouter de Laat","doi":"10.1101/gad.352235.124","DOIUrl":"https://doi.org/10.1101/gad.352235.124","url":null,"abstract":"Enhancers are tissue-specific regulatory DNA elements that can activate transcription of genes over distance. Their target genes most often are located in the same contact domain—chromosomal entities formed by cohesin DNA loop extrusion and typically flanked by CTCF-bound boundaries. Enhancers shared by multiple unrelated genes are underexplored but may be more common than anticipated. Here, we analyzed the interplay between an enhancer and two distal functionally unrelated genes residing at opposite domain boundaries. The enhancer strongly activated their expression and supported their frequent interactions. Cohesin structured the domain and supported their transcription, but the genes did not rely on each other's transcription or show gene competition. Deleting either domain boundary not only extended the contact domain but led to reduced contacts within the original domain and reduction in the expression of both genes. Conversely, by isolating either gene with the enhancer in shorter domains, through insertion of new CTCF boundaries, intradomain contact frequencies increased, and the gene isolated with the enhancer was upregulated. Collectively, this shows that an enhancer can independently activate unrelated distal genes and that long-range gene regulation benefits from operating in small contact domains.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"20 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044068","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}

引用次数: 0

LINE-1, the NORth star of nucleolar organization 线-1，核仁组织的北极星

IF 10.5 1区生物学

Genes & development Pub Date : 2025-01-10 DOI: 10.1101/gad.352583.124

Misaki Matsuo, Gael Cristofari

引用次数: 0

ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation ESRP2-microRNA-122轴促进出生后肝脏多倍体和成熟的发生

IF 10.5 1区生物学

Genes & development Pub Date : 2025-01-10 DOI: 10.1101/gad.352129.124

Sushant Bangru, Jackie Chen, Nicholas Baker, Diptatanu Das, Ullas V. Chembazhi, Jessica M. Derham, Sandip Chorghade, Waqar Arif, Frances Alencastro, Andrew W. Duncan, Russ P. Carstens, Auinash Kalsotra

{"title":"ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation","authors":"Sushant Bangru, Jackie Chen, Nicholas Baker, Diptatanu Das, Ullas V. Chembazhi, Jessica M. Derham, Sandip Chorghade, Waqar Arif, Frances Alencastro, Andrew W. Duncan, Russ P. Carstens, Auinash Kalsotra","doi":"10.1101/gad.352129.124","DOIUrl":"https://doi.org/10.1101/gad.352129.124","url":null,"abstract":"Hepatocyte polyploidy and maturity are critical to acquiring specialized liver functions. Multiple intracellular and extracellular factors influence ploidy, but how they cooperate temporally to steer liver polyploidization and maturation or how post-transcriptional mechanisms integrate into these paradigms is unknown. Here, we identified an important regulatory hierarchy in which postnatal activation of epithelial splicing regulatory protein 2 (ESRP2) stimulates processing of liver-specific microRNA (miR-122) to facilitate polyploidization, maturation, and functional competence of hepatocytes. By determining transcriptome-wide protein–RNA interactions in vivo and integrating them with single-cell and bulk hepatocyte RNA-seq data sets, we delineated an ESRP2-driven RNA processing program that drives sequential replacement of fetal-to-adult transcript isoforms. Specifically, ESRP2 binds the primary miR-122 host gene transcript to promote its processing/biogenesis. Combining constitutive and inducible ESRP2 gain- and loss-of-function mouse models with miR-122 rescue experiments, we demonstrated that timed activation of ESRP2 augments the miR-122-driven program of cytokinesis failure, ensuring the proper onset and extent of hepatocyte polyploidization.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"319 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961765","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}

引用次数: 0

Deciphering normal and cancer stem cell niches by spatial transcriptomics: opportunities and challenges. 通过空间转录组学解读正常和癌症干细胞龛位：机遇与挑战。

IF 7.5 1区生物学

Genes & development Pub Date : 2025-01-07 DOI: 10.1101/gad.351956.124

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":"10.1101/gad.351956.124","url":null,"abstract":"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.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"64-85"},"PeriodicalIF":7.5,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11789490/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genes & Development aims for an expansive horizon 基因与发展的目标是一个广阔的视野

IF 10.5 1区生物学

Genes & development Pub Date : 2025-01-01 DOI: 10.1101/gad.352534.124

Andrew Dillin

引用次数: 0

Genes & Development: an evolution 基因与发育：一种进化

IF 10.5 1区生物学

Genes & development Pub Date : 2025-01-01 DOI: 10.1101/gad.352552.124

John R. Inglis

引用次数: 0

E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β cells E3连接酶底物适配器SPOP微调胰腺β细胞的UPR

IF 10.5 1区生物学

Genes & development Pub Date : 2024-12-30 DOI: 10.1101/gad.352010.124

Alexis U. Oguh, Matthew W. Haemmerle, Sabyasachi Sen, Andrea V. Rozo, Shristi Shrestha, Jean-Philippe Cartailler, Hossein Fazelinia, Hua Ding, Sam Preza, Juxiang Yang, Xiaodun Yang, Lori Sussel, Juan R. Alvarez-Dominguez, Nicolai Doliba, Lynn A. Spruce, Rafael Arrojo e Drigo, Doris A. Stoffers

{"title":"E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β cells","authors":"Alexis U. Oguh, Matthew W. Haemmerle, Sabyasachi Sen, Andrea V. Rozo, Shristi Shrestha, Jean-Philippe Cartailler, Hossein Fazelinia, Hua Ding, Sam Preza, Juxiang Yang, Xiaodun Yang, Lori Sussel, Juan R. Alvarez-Dominguez, Nicolai Doliba, Lynn A. Spruce, Rafael Arrojo e Drigo, Doris A. Stoffers","doi":"10.1101/gad.352010.124","DOIUrl":"https://doi.org/10.1101/gad.352010.124","url":null,"abstract":"The Cullin-3 E3 ligase adaptor protein SPOP targets proteins for ubiquitination and proteasomal degradation. We previously established the β-cell transcription factor (TF) and human diabetes gene PDX1 as an SPOP substrate, suggesting a functional role for SPOP in the β cell. Here, we generated a β-cell-specific Spop deletion mouse strain (SpopβKO) and found that Spop is necessary to prevent aberrant basal insulin secretion and for maintaining glucose-stimulated insulin secretion through impacts on glycolysis and glucose-stimulated calcium flux. Integration of proteomic, TF-regulatory gene network, and biochemical analyses identified XBP1 as a functionally important SPOP substrate in pancreatic β cells. Furthermore, loss of SPOP strengthened the IRE1α–XBP1 axis of unfolded protein response (UPR) signaling. ER stress promoted proteasomal degradation of SPOP, supporting a model whereby SPOP fine-tunes XBP1 activation during the UPR. These results position SPOP as a regulator of β-cell function and proper UPR activation.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"36 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901764","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}

引用次数: 0

Alternative splicing controls pan-neuronal homeobox gene expression 选择性剪接控制泛神经元同源盒基因表达

IF 10.5 1区生物学

Genes & development Pub Date : 2024-12-27 DOI: 10.1101/gad.352184.124

Eduardo Leyva-Díaz, Michael Cesar, Karinna Pe, José Ignacio Jordá-Llorens, Jessica Valdivia, Oliver Hobert

{"title":"Alternative splicing controls pan-neuronal homeobox gene expression","authors":"Eduardo Leyva-Díaz, Michael Cesar, Karinna Pe, José Ignacio Jordá-Llorens, Jessica Valdivia, Oliver Hobert","doi":"10.1101/gad.352184.124","DOIUrl":"https://doi.org/10.1101/gad.352184.124","url":null,"abstract":"The pan-neuronally expressed and phylogenetically conserved CUT homeobox gene ceh-44/CUX orchestrates pan-neuronal gene expression throughout the nervous system of Caenorhabditis elegans. As in many other species, including humans, ceh-44/CUX is encoded by a complex locus that also codes for a Golgi-localized protein, called CASP (Cux1 alternatively spliced product) in humans and CONE-1 (“CASP of nematodes”) in C. elegans. How gene expression from this complex locus is controlled—and, in C. elegans, directed to all cells of the nervous system—has not been investigated. We show here that pan-neuronal expression of CEH-44/CUX is controlled by a pan-neuronal RNA splicing factor, UNC-75, the C. elegans homolog of vertebrate CELF proteins. During embryogenesis, the cone-1&ceh-44 locus exclusively produces the Golgi-localized CONE-1/CASP protein in all tissues, but upon the onset of postmitotic terminal differentiation of neurons, UNC-75/CELF induces the production of the alternative CEH-44/CUX CUT homeobox gene-encoding transcript exclusively in the nervous system. Hence, UNC-75/CELF-mediated alternative splicing not only directs pan-neuronal gene expression but also excludes a phylogenetically deeply conserved golgin from the nervous system, paralleling surprising spatial specificities of another golgin that we describe here as well. Our findings provide novel insights into how all cells in a nervous system acquire pan-neuronal identity features and reveal unanticipated cellular specificities in Golgi apparatus composition.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"15 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887883","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}

引用次数: 0