Genes & development最新文献_第7页

Oct4 redox sensitivity potentiates reprogramming and differentiation Oct4 氧化还原敏感性可促进重编程和分化

IF 10.5 1区生物学

Genes & development Pub Date : 2024-05-07 DOI: 10.1101/gad.351411.123

Zuolian Shen, Yifan Wu, Asit Manna, Chongil Yi, Bradley R. Cairns, Kimberley J. Evason, Mahesh B. Chandrasekharan, Dean Tantin

{"title":"Oct4 redox sensitivity potentiates reprogramming and differentiation","authors":"Zuolian Shen, Yifan Wu, Asit Manna, Chongil Yi, Bradley R. Cairns, Kimberley J. Evason, Mahesh B. Chandrasekharan, Dean Tantin","doi":"10.1101/gad.351411.123","DOIUrl":"https://doi.org/10.1101/gad.351411.123","url":null,"abstract":"The transcription factor Oct4/Pou5f1 is a component of the regulatory circuitry governing pluripotency and is widely used to induce pluripotency from somatic cells. Here we used domain swapping and mutagenesis to study Oct4's reprogramming ability, identifying a redox-sensitive DNA binding domain, cysteine residue (Cys48), as a key determinant of reprogramming and differentiation. Oct4 Cys48 sensitizes the protein to oxidative inhibition of DNA binding activity and promotes oxidation-mediated protein ubiquitylation. Pou5f1C48S point mutation has little effect on undifferentiated embryonic stem cells (ESCs) but upon retinoic acid (RA) treatment causes retention of Oct4 expression, deregulated gene expression, and aberrant differentiation. Pou5f1C48S ESCs also form less differentiated teratomas and contribute poorly to adult somatic tissues. Finally, we describe Pou5f1C48S (Janky) mice, which in the homozygous condition are severely developmentally restricted after E4.5. Rare animals bypassing this restriction appear normal at birth but are sterile. Collectively, these findings uncover a novel Oct4 redox mechanism involved in both entry into and exit from pluripotency.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"10 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140845546","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

The lncRNA Malat1 is trafficked to the cytoplasm as a localized mRNA encoding a small peptide in neurons 在神经元中，lncRNA Malat1 作为编码小肽的局部 mRNA 被运输到细胞质中

IF 10.5 1区生物学

Genes & development Pub Date : 2024-04-30 DOI: 10.1101/gad.351557.124

Wen Xiao, Reem Halabi, Chia-Ho Lin, Mohammad Nazim, Kyu-Hyeon Yeom, Douglas L. Black

{"title":"The lncRNA Malat1 is trafficked to the cytoplasm as a localized mRNA encoding a small peptide in neurons","authors":"Wen Xiao, Reem Halabi, Chia-Ho Lin, Mohammad Nazim, Kyu-Hyeon Yeom, Douglas L. Black","doi":"10.1101/gad.351557.124","DOIUrl":"https://doi.org/10.1101/gad.351557.124","url":null,"abstract":"Synaptic function in neurons is modulated by local translation of mRNAs that are transported to distal portions of axons and dendrites. The metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) is broadly expressed across cell types, almost exclusively as a nuclear long noncoding RNA. We found that in differentiating neurons, a portion of Malat1 RNA redistributes to the cytoplasm. Depletion of Malat1 using antisense oligonucleotides (ASOs) stimulates the expression of particular pre- and postsynaptic proteins, implicating Malat1 in their regulation. Neuronal Malat1 is localized in puncta of both axons and dendrites that costain with Staufen1 protein, similar to neuronal RNA granules formed by locally translated mRNAs. Ribosome profiling of cultured mouse cortical neurons identified ribosome footprints within a 5′ region of Malat1 containing short open reading frames. The upstream-most reading frame (M1) of the Malat1 locus was linked to the GFP-coding sequence in mouse embryonic stem cells. When these gene-edited cells were differentiated into glutamatergic neurons, the M1-GFP fusion protein was expressed. Antibody staining for the M1 peptide confirmed its presence in wild-type neurons and showed that M1 expression was enhanced by synaptic stimulation with KCl. Our results indicate that Malat1 serves as a cytoplasmic coding RNA in the brain that is both modulated by and modulates synaptic function.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"146 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140814383","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

An unexpected path for Malat1 in neurons: trafficking out of the nucleus for translation 神经元中 Malat1 的意外之路：运出细胞核进行翻译

IF 10.5 1区生物学

Genes & development Pub Date : 2024-04-30 DOI: 10.1101/gad.351820.124

Bradley W. Wright, Jeremy E. Wilusz

引用次数: 0

Haploinsufficiency of phosphodiesterase 10A activates PI3K/AKT signaling independent of PTEN to induce an aggressive glioma phenotype 磷酸二酯酶 10A 的单倍体缺陷可激活 PI3K/AKT 信号，而不依赖于 PTEN，从而诱发侵袭性胶质瘤表型

IF 10.5 1区生物学

Genes & development Pub Date : 2024-04-08 DOI: 10.1101/gad.351350.123

Nicholas Nuechterlein, Allison Shelbourn, Frank Szulzewsky, Sonali Arora, Michelle Casad, Siobhan Pattwell, Leyre Merino-Galan, Erik Sulman, Sumaita Arowa, Neriah Alvinez, Miyeon Jung, Desmond Brown, Kayen Tang, Sadhana Jackson, Stefan Stoica, Prashant Chittaboina, Yeshavanth K. Banasavadi-Siddegowda, Hans-Georg Wirsching, Nephi Stella, Linda Shapiro, Patrick Paddison, Anoop P. Patel, Mark R. Gilbert, Zied Abdullaev, Kenneth Aldape, Drew Pratt, Eric C. Holland, Patrick J. Cimino

{"title":"Haploinsufficiency of phosphodiesterase 10A activates PI3K/AKT signaling independent of PTEN to induce an aggressive glioma phenotype","authors":"Nicholas Nuechterlein, Allison Shelbourn, Frank Szulzewsky, Sonali Arora, Michelle Casad, Siobhan Pattwell, Leyre Merino-Galan, Erik Sulman, Sumaita Arowa, Neriah Alvinez, Miyeon Jung, Desmond Brown, Kayen Tang, Sadhana Jackson, Stefan Stoica, Prashant Chittaboina, Yeshavanth K. Banasavadi-Siddegowda, Hans-Georg Wirsching, Nephi Stella, Linda Shapiro, Patrick Paddison, Anoop P. Patel, Mark R. Gilbert, Zied Abdullaev, Kenneth Aldape, Drew Pratt, Eric C. Holland, Patrick J. Cimino","doi":"10.1101/gad.351350.123","DOIUrl":"https://doi.org/10.1101/gad.351350.123","url":null,"abstract":"Glioblastoma is universally fatal and characterized by frequent chromosomal copy number alterations harboring oncogenes and tumor suppressors. In this study, we analyzed exome-wide human glioblastoma copy number data and found that cytoband 6q27 is an independent poor prognostic marker in multiple data sets. We then combined CRISPR–Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate PDE10A as a potential haploinsufficient tumor suppressor in the 6q27 region. Mouse glioblastoma modeling using the RCAS/tv-a system confirmed that Pde10a suppression induced an aggressive glioma phenotype in vivo and resistance to temozolomide and radiation therapy in vitro. Cell culture analysis showed that decreased Pde10a expression led to increased PI3K/AKT signaling in a Pten-independent manner, a response blocked by selective PI3K inhibitors. Single-nucleus RNA sequencing from our mouse gliomas in vivo, in combination with cell culture validation, further showed that Pde10a suppression was associated with a proneural-to-mesenchymal transition that exhibited increased cell adhesion and decreased cell migration. Our results indicate that glioblastoma patients harboring PDE10A loss have worse outcomes and potentially increased sensitivity to PI3K inhibition.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"56 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534304","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

A germline point mutation in the MYC-FBW7 phosphodegron initiates hematopoietic malignancies MYC-FBW7 phosphodegron 的种系点突变引发造血恶性肿瘤

IF 10.5 1区生物学

Genes & development Pub Date : 2024-04-02 DOI: 10.1101/gad.351292.123

Brian Freie, Patrick A. Carroll, Barbara J. Varnum-Finney, Erin L. Ramsey, Vijay Ramani, Irwin Bernstein, Robert N. Eisenman

{"title":"A germline point mutation in the MYC-FBW7 phosphodegron initiates hematopoietic malignancies","authors":"Brian Freie, Patrick A. Carroll, Barbara J. Varnum-Finney, Erin L. Ramsey, Vijay Ramani, Irwin Bernstein, Robert N. Eisenman","doi":"10.1101/gad.351292.123","DOIUrl":"https://doi.org/10.1101/gad.351292.123","url":null,"abstract":"Oncogenic activation of MYC in cancers predominantly involves increased transcription rather than coding region mutations. However, MYC-dependent lymphomas frequently acquire point mutations in the MYC phosphodegron, including at threonine 58 (T58), where phosphorylation permits binding via the FBW7 ubiquitin ligase triggering MYC degradation. To understand how T58 phosphorylation functions in normal cell physiology, we introduced an alanine mutation at T58 (T58A) into the endogenous c-Myc locus in the mouse germline. While MYC-T58A mice develop normally, lymphomas and myeloid leukemias emerge in ∼60% of adult homozygous T58A mice. We found that primitive hematopoietic progenitor cells from MYC-T58A mice exhibit aberrant self-renewal normally associated with hematopoietic stem cells (HSCs) and up-regulate a subset of MYC target genes important in maintaining stem/progenitor cell balance. In lymphocytes, genomic occupancy by MYC-T58A was increased at all promoters compared with WT MYC, while genes differentially expressed in a T58A-dependent manner were significantly more proximal to MYC-bound enhancers. MYC-T58A lymphocyte progenitors exhibited metabolic alterations and decreased activation of inflammatory and apoptotic pathways. Our data demonstrate that a single point mutation stabilizing MYC is sufficient to skew target gene expression, producing a profound gain of function in multipotential hematopoietic progenitors associated with self-renewal and initiation of lymphomas and leukemias.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"130 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534443","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

Corrigendum: miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma. 更正：miR-182 整合了胶质母细胞瘤的凋亡、生长和分化程序。

IF 10.5 1区生物学

Genes & development Pub Date : 2024-04-01 DOI: 10.1101/gad.351832.124

Fotini M Kouri, Lisa A Hurley, Weston L Daniel, Emily S Day, Youjia Hua, Liangliang Hao, Chian-Yu Peng, Timothy J Merkel, Markus A Queisser, Carissa Ritner, Hailei Zhang, C David James, Jacob I Sznajder, Lynda Chin, David A Giljohann, John A Kessler, Marcus E Peter, Chad A Mirkin, Alexander H Stegh

引用次数: 0

Corrigendum: Defining the influence of Rad51 and Dmc1 lineage-specific amino acids on genetic recombination. 更正：确定 Rad51 和 Dmc1 行系特异性氨基酸对基因重组的影响。

IF 10.5 1区生物学

Genes & development Pub Date : 2024-04-01 DOI: 10.1101/gad.351813.124

Justin B Steinfeld, Ondrej Beláň, Youngho Kwon, Tsuyoshi Terakawa, Amr Al-Zain, Michael J Smith, J Brooks Crickard, Zhi Qi, Weixing Zhao, Rodney Rothstein, Lorraine S Symington, Patrick Sung, Simon J Boulton, Eric C Greene

引用次数: 0

A serine metabolic enzyme is flexing its muscle to help repair skeletal muscle. 一种丝氨酸代谢酶正在发挥它的作用，帮助修复骨骼肌。

IF 7.5 1区生物学

Genes & development Pub Date : 2024-03-22 DOI: 10.1101/gad.351666.124

Benjámin R Baráth, Laszlo Nagy

引用次数: 0

Pan-cellular organelles and suborganelles-from common functions to cellular diversity? 泛细胞器和亚细胞器--从共同功能到细胞多样性？

IF 7.5 1区生物学

Genes & development Pub Date : 2024-03-22 DOI: 10.1101/gad.351337.123

Rico Schieweck, Magdalena Götz

{"title":"Pan-cellular organelles and suborganelles-from common functions to cellular diversity?","authors":"Rico Schieweck, Magdalena Götz","doi":"10.1101/gad.351337.123","DOIUrl":"10.1101/gad.351337.123","url":null,"abstract":"Cell diversification is at the base of increasing multicellular organism complexity in phylogeny achieved during ontogeny. However, there are also functions common to all cells, such as cell division, cell migration, translation, endocytosis, exocytosis, etc. Here we revisit the organelles involved in such common functions, reviewing recent evidence of unexpected differences of proteins at these organelles. For instance, centrosomes or mitochondria differ significantly in their protein composition in different, sometimes closely related, cell types. This has relevance for development and disease. Particularly striking is the high amount and diversity of RNA-binding proteins at these and other organelles, which brings us to review the evidence for RNA at different organelles and suborganelles. We include a discussion about (sub)organelles involved in translation, such as the nucleolus and ribosomes, for which unexpected cell type-specific diversity has also been reported. We propose here that the heterogeneity of these organelles and compartments represents a novel mechanism for regulating cell diversity. One reason is that protein functions can be multiplied by their different contributions in distinct organelles, as also exemplified by proteins with moonlighting function. The specialized organelles still perform pan-cellular functions but in a cell type-specific mode, as discussed here for centrosomes, mitochondria, vesicles, and other organelles. These can serve as regulatory hubs for the storage and transport of specific and functionally important regulators. In this way, they can control cell differentiation, plasticity, and survival. We further include examples highlighting the relevance for disease and propose to examine organelles in many more cell types for their possible differences with functional relevance.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"98-114"},"PeriodicalIF":7.5,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10982711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140131203","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

A maternal-effect Padi6 variant causes nuclear and cytoplasmic abnormalities in oocytes, as well as failure of epigenetic reprogramming and zygotic genome activation in embryos. 母体效应 Padi6 变体会导致卵母细胞的细胞核和细胞质异常，以及胚胎表观遗传重编程和子代基因组激活失败。

IF 7.5 1区生物学

Genes & development Pub Date : 2024-03-22 DOI: 10.1101/gad.351238.123

Carlo Giaccari, Francesco Cecere, Lucia Argenziano, Angela Pagano, Antonio Galvao, Dario Acampora, Gianna Rossi, Bruno Hay Mele, Basilia Acurzio, Scott Coonrod, Maria Vittoria Cubellis, Flavia Cerrato, Simon Andrews, Sandra Cecconi, Gavin Kelsey, Andrea Riccio

{"title":"A maternal-effect Padi6 variant causes nuclear and cytoplasmic abnormalities in oocytes, as well as failure of epigenetic reprogramming and zygotic genome activation in embryos.","authors":"Carlo Giaccari, Francesco Cecere, Lucia Argenziano, Angela Pagano, Antonio Galvao, Dario Acampora, Gianna Rossi, Bruno Hay Mele, Basilia Acurzio, Scott Coonrod, Maria Vittoria Cubellis, Flavia Cerrato, Simon Andrews, Sandra Cecconi, Gavin Kelsey, Andrea Riccio","doi":"10.1101/gad.351238.123","DOIUrl":"10.1101/gad.351238.123","url":null,"abstract":"Maternal inactivation of genes encoding components of the subcortical maternal complex (SCMC) and its associated member, PADI6, generally results in early embryo lethality. In humans, SCMC gene variants were found in the healthy mothers of children affected by multilocus imprinting disturbances (MLID). However, how the SCMC controls the DNA methylation required to regulate imprinting remains poorly defined. We generated a mouse line carrying a Padi6 missense variant that was identified in a family with Beckwith-Wiedemann syndrome and MLID. If homozygous in female mice, this variant resulted in interruption of embryo development at the two-cell stage. Single-cell multiomic analyses demonstrated defective maturation of Padi6 mutant oocytes and incomplete DNA demethylation, down-regulation of zygotic genome activation (ZGA) genes, up-regulation of maternal decay genes, and developmental delay in two-cell embryos developing from Padi6 mutant oocytes but little effect on genomic imprinting. Western blotting and immunofluorescence analyses showed reduced levels of UHRF1 in oocytes and abnormal localization of DNMT1 and UHRF1 in both oocytes and zygotes. Treatment with 5-azacytidine reverted DNA hypermethylation but did not rescue the developmental arrest of mutant embryos. Taken together, this study demonstrates that PADI6 controls both nuclear and cytoplasmic oocyte processes that are necessary for preimplantation epigenetic reprogramming and ZGA.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"131-150"},"PeriodicalIF":7.5,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10982689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059112","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