Genes & development最新文献_第10页

A lncRNA drives developmentally timed decay of all members of an essential microRNA family. lncRNA驱动一个基本microRNA家族所有成员的发育时间衰减。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-05-04 DOI: 10.1101/gad.353314.125

Acadia L Grimme, Lu Li, Alyshia Scholl, Bridget F Donnelly, Neha Channamraju, Karl-Frédéric Vieux, Lecong Zhou, Geraldine Seydoux, Mingyi Xie, Katherine McJunkin

{"title":"A lncRNA drives developmentally timed decay of all members of an essential microRNA family.","authors":"Acadia L Grimme, Lu Li, Alyshia Scholl, Bridget F Donnelly, Neha Channamraju, Karl-Frédéric Vieux, Lecong Zhou, Geraldine Seydoux, Mingyi Xie, Katherine McJunkin","doi":"10.1101/gad.353314.125","DOIUrl":"10.1101/gad.353314.125","url":null,"abstract":"The spatiotemporal expression patterns of microRNAs (miRNAs) are crucial to their function. Target-directed miRNA degradation (TDMD) is an emerging regulatory module that contributes to these expression patterns wherein a specialized RNA (a TDMD trigger) drives miRNA decay through base pairing and the resulting recruitment of E3 ubiquitin ligase ZSWIM8/EBAX-1. Extensive base pairing to the miRNA seed region and 3' end has been proposed as a key feature that distinguishes TDMD triggers from conventional mRNA targets of miRNAs, which primarily pair with the seed. Here we identify the long noncoding RNA tts-2 as a TDMD trigger for mir-35-42, the most abundant miRNA family in Caenorhabditis elegans early embryos. We demonstrate that a single site in tts-2 drives decay through base pairing with the seed sequence shared by all eight family members. A second site in tts-2 supports decay of mir-38 with incomplete seed complementarity. Retargeting tts-2 to other miRNAs suggests that the GC-rich seed of mir-35-42 allows for seed-sufficient TDMD. Our findings demonstrate that extended base pairing is not a universal requirement of TDMD and that TDMD drives developmentally timed clearance of abundant miRNAs at the exit of C. elegans embryogenesis.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"737-755"},"PeriodicalIF":7.4,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13115287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147369305","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

α-Satellite RNA marks the perinucleolar compartment and represses ribosomal RNA expression in naive human embryonic stem cells. α-卫星RNA在人胚胎干细胞中标记核周室并抑制核糖体RNA的表达。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-05-04 DOI: 10.1101/gad.353162.125

Kirti Mittal, Lamisa Ataei, Miguel Ramalho-Santos

{"title":"α-Satellite RNA marks the perinucleolar compartment and represses ribosomal RNA expression in naive human embryonic stem cells.","authors":"Kirti Mittal, Lamisa Ataei, Miguel Ramalho-Santos","doi":"10.1101/gad.353162.125","DOIUrl":"10.1101/gad.353162.125","url":null,"abstract":"While most newly synthesized RNA is exported to the cytoplasm, a portion of noncoding RNA is retained in the nucleus and remains highly associated with chromatin. The strong binding of this RNA fraction to insoluble chromatin impairs its recovery in standard transcriptomic studies. Therefore, the landscape and potential functions of chromatin-associated RNAs are poorly understood. Recent studies indicate that chromatin-associated transcripts can have regulatory roles, particularly during mammalian development. Here we compare the dynamics of cytoplasmic versus chromatin-bound transcriptomes of naive and primed human embryonic stem cells (hESCs) as well as fibroblasts. We found a remarkable enrichment for RNA transcribed from α-satellite repeat (ALR) in the chromatin fraction of naive hESCs compared with primed hESCs. The colocalization and interaction of ALR RNA with polypyrimidine tract binding protein 1 (PTBP1) and CUG-binding protein (CUGBP) indicate that ALR RNA foci mark the perinucleolar compartment (PNC), a nuclear subcompartment previously thought to be exclusive to cancer cells. Knockdown of ALR RNA leads to dispersion of PTBP1/CUGBP foci, upregulation of ribosomal RNA, and global hypertranscription in naive hESCs. In contrast, loss of PTBP1 does not disturb ALR RNA localization, indicating that ALR is upstream in the hierarchy of organization of the PNC in hESCs. These results reveal a role for ALR RNA in nuclear compartmentalization and tuning rRNA synthesis in naive hESCs. Moreover, this study opens new avenues to dissect the function of ALR RNA and the PNC in cancer contexts.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"717-736"},"PeriodicalIF":7.4,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147276019","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 conserved N-terminal SANT1-binding domain (SBD) of EZH2 regulates PRC2 activity. EZH2的保守n端sant1结合域（SBD）调控PRC2活性。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-05-04 DOI: 10.1101/gad.353070.125

Agata L Patriotis, Douglas W Barrows, Yadira Soto-Feliciano, Laiba F Khan, Marylene Leboeuf, Dylan M Marchione, Matthew R Marunde, Michael-Christopher Keogh, Thomas S Carroll, Benjamin A Garcia, Alexey A Soshnev, C David Allis

{"title":"The conserved N-terminal SANT1-binding domain (SBD) of EZH2 regulates PRC2 activity.","authors":"Agata L Patriotis, Douglas W Barrows, Yadira Soto-Feliciano, Laiba F Khan, Marylene Leboeuf, Dylan M Marchione, Matthew R Marunde, Michael-Christopher Keogh, Thomas S Carroll, Benjamin A Garcia, Alexey A Soshnev, C David Allis","doi":"10.1101/gad.353070.125","DOIUrl":"10.1101/gad.353070.125","url":null,"abstract":"Polycomb group proteins maintain gene expression patterns established during early development, with Polycomb repressive complex 2 (PRC2) methyltransferase being a key regulator of cell differentiation, identity, and plasticity. Consequently, extensive somatic mutations in PRC2, including gain or loss of function (GOF or LOF), are observed in human cancers. The regulation of chromatin structure by PRC2 is critically dependent on its enhancer of zeste homolog 2 (EZH2) subunit, which catalyzes the methylation of histone H3 lysine 27 (H3K27). Recent structural studies of PRC2 revealed extensive conformational changes in the noncatalytic EZH2 N-terminal SANT1-binding domain (SBD) during PRC2 activation, though the functional significance remains unclear. Here, we investigated how the SBD regulates PRC2 function. The domain is highly conserved in metazoans and dispensable for PRC2 assembly and chromatin localization yet is required for genome-wide histone H3K27 methylation. Furthermore, we show that an intact SBD is necessary for the proliferation of EZH2-addicted lymphomas, and its deletion in the presence of EZH2 GOF mutations inhibits cancer cell growth. These observations provide new insights into the regulation of PRC2 activity in normal development and malignancy.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"650-665"},"PeriodicalIF":7.4,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13138334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149507","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

Loss of the tumor suppressor PTEN activates cell-intrinsic interferon signaling to drive immune resistance. 肿瘤抑制因子PTEN的缺失会激活细胞内禀干扰素信号，从而驱动免疫抵抗。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-05-04 DOI: 10.1101/gad.353283.125

Yubao Wang, Cherubin Manokaran, Yutian Zou, Jiajia Chen, Hao Gu, David Liu, Philippe Bousso, Jean J Zhao, Thomas M Roberts

{"title":"Loss of the tumor suppressor PTEN activates cell-intrinsic interferon signaling to drive immune resistance.","authors":"Yubao Wang, Cherubin Manokaran, Yutian Zou, Jiajia Chen, Hao Gu, David Liu, Philippe Bousso, Jean J Zhao, Thomas M Roberts","doi":"10.1101/gad.353283.125","DOIUrl":"10.1101/gad.353283.125","url":null,"abstract":"Loss of the tumor suppressor PTEN is strongly associated with a lack of response to immune checkpoint blockade therapies in cancer patients, but the underlying mechanisms are not fully understood. We have developed a transformation model where knocking out PTEN in human mammary epithelial cells drives dependence on the p110β subunit of PI3K and, notably, elicits a robust induction of endogenous retroviral elements (ERVs) and activation of interferon signaling. This constitutive cell-intrinsic interferon response, hallmarked by hyperactivated STAT1, is also observed in human tumors with a PTEN-low status. We further found that PTEN deficiency renders cancer cells resistant to the cytotoxic effects of immune cells and interferon-γ. Notably, PTEN loss also results in a dependency on an activated DNA damage response pathway, leading to an exquisite vulnerability to CDK12 inhibition. Our study suggests an interferon adaptation model in which tumors driven by PTEN deficiency inherently activate the interferon response, enabling them to adapt to interferon cytotoxicity and gain resistance to immunotherapies.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"684-698"},"PeriodicalIF":7.4,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13367035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146219329","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

Chromatin binding and N-terminal domains of DNMT3B1 confer specificity for developmentally regulated CpG island methylation. 染色质结合和DNMT3B1的n端结构域赋予了发育调节CpG岛甲基化的特异性。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-05-04 DOI: 10.1101/gad.353014.125

Komal Yasmin, Tatyana B Nesterova, Neil Brockdorff

{"title":"Chromatin binding and N-terminal domains of DNMT3B1 confer specificity for developmentally regulated CpG island methylation.","authors":"Komal Yasmin, Tatyana B Nesterova, Neil Brockdorff","doi":"10.1101/gad.353014.125","DOIUrl":"10.1101/gad.353014.125","url":null,"abstract":"CpG methylation in mammalian genomes is established by the closely related de novo DNA methyltransferases DNMT3A and DNMT3B. While both enzymes contribute to genome-wide CpG methylation, DNMT3B has a unique role in developmentally regulated CpG island (CGI) methylation on the inactive X chromosome and at other sites in the genome. The mechanistic basis for this specificity is poorly understood. Here we have developed an in vitro embryonic stem cell model system to dissect critical determinants of DNMT3B specificity. Our model faithfully recapitulates developmentally regulated CGI methylation and additionally provides novel insights into CpG methylation at cis-regulatory elements. Using genetic complementation, we show that DNMT3B specificity is attributable solely to the major catalytic isoform DNMT3B1. Domain swap experiments demonstrate a role for the PWWP-ADD chromatin binding domains, while deletion analysis reveals the importance of the unstructured N-terminal domain, including a requirement for a specific subregion in CGI methylation on Xi. Together, these findings advance our mechanistic understanding of the unique roles of DNMT3 enzymes in establishing CpG methylation in development.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"666-683"},"PeriodicalIF":7.4,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13138329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165019","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

Linking miRNAs to decay. 连接mirna与衰变。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-05-04 DOI: 10.1101/gad.353649.126

Amy E Pasquinelli

引用次数: 0

Multiomic analysis of clonal development reveals new regulators of leukemic cell growth. 克隆发育的多组学分析揭示白血病细胞生长的新调控因子。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-04-01 DOI: 10.1101/gad.353186.125

Gracia Bonilla, Alexander Morris, Sharmistha Kundu, Anthony DuCasse, Grace Kirkpatrick, Jelena Milosevic, Nathan E Jeffries, Kashish Chetal, Emma E Yvanovich, Ting Zhao, Jun Xia, Rana Barghout, David Scadden, Michael K Mansour, Robert E Kingston, David B Sykes, Francois E Mercier, Ruslan I Sadreyev

{"title":"Multiomic analysis of clonal development reveals new regulators of leukemic cell growth.","authors":"Gracia Bonilla, Alexander Morris, Sharmistha Kundu, Anthony DuCasse, Grace Kirkpatrick, Jelena Milosevic, Nathan E Jeffries, Kashish Chetal, Emma E Yvanovich, Ting Zhao, Jun Xia, Rana Barghout, David Scadden, Michael K Mansour, Robert E Kingston, David B Sykes, Francois E Mercier, Ruslan I Sadreyev","doi":"10.1101/gad.353186.125","DOIUrl":"10.1101/gad.353186.125","url":null,"abstract":"Mechanisms driving the increase in cell growth in developing leukemia are not fully understood. We focused on epigenomic regulation of this process by analyzing the changes of chromatin marks and gene expression in leukemic cell clones as they progressed toward increased proliferation in a mouse model of acute myeloid leukemia (AML). This progression was characterized by gradual modulation of chromatin states and gene expression across the genome, with a surprising preferential trend of reversing the prior changes associated with the origins of leukemia. Our analyses of this modulation in independently developing clones predicted a small set of potential growth regulators whose transcriptomic and epigenomic progression was consistent between clones and maintained both in vivo and ex vivo. We selected three of these genes as candidates (Irx5 and Plag1 as growth suppressors and Smad1 as a driver) and successfully validated their causal growth effects by overexpression in mouse leukemic cells. Overexpression of the IRX5 gene in human MOLM13 leukemic cells suppressed cell growth both in vitro and in mouse xenografts. Public patient data confirmed expression levels of PLAG1 and SMAD1 as markers of AML status and survival, suggesting that multiomic analysis of evolving clones in a mouse model is a valuable predictive approach relevant to human AML.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"563-585"},"PeriodicalIF":7.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13041715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118722","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

Bypass of blocking lesions by RNAPII reveals a novel stress induced by DNA damage. RNAPII旁路阻断病变揭示了由DNA损伤引起的一种新的应激。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-04-01 DOI: 10.1101/gad.353164.125

Carolina P Bañuelos, Lucas D Caeiro, Pradeepkumar R Cingaram, Felipe Beckedorff, Lluis Morey, Daniel Bilbao Cortes, Ramin Shiekhattar, Ramiro E Verdun

{"title":"Bypass of blocking lesions by RNAPII reveals a novel stress induced by DNA damage.","authors":"Carolina P Bañuelos, Lucas D Caeiro, Pradeepkumar R Cingaram, Felipe Beckedorff, Lluis Morey, Daniel Bilbao Cortes, Ramin Shiekhattar, Ramiro E Verdun","doi":"10.1101/gad.353164.125","DOIUrl":"10.1101/gad.353164.125","url":null,"abstract":"Platinum-based compounds and ultraviolet (UV) irradiation produce bulky DNA lesions that stall RNA polymerase II (RNAPII), activating transcription-coupled nucleotide excision repair (TC-NER), RNAPII degradation, and global transcriptional shutdown. However, the consequences of RNAPII bypassing such lesions remain unclear. We identified the acetyltransferase p300 as a key regulator of TC-NER-dependent RNAPII removal from damaged chromatin via a USP7-dependent mechanism. Loss of p300 permits RNAPII to bypass transcription-blocking lesions, sustaining transcription and full-length mRNA production despite DNA damage. This leads to continued translation, endoplasmic reticulum (ER) stress, and activation of the unfolded protein response (UPR), compromising cell viability. Notably, this stress response resensitizes tumors resistant to platinum-based chemotherapy. Our findings reveal a vulnerability in tumor cells that evade transcriptional shutdown and define a synthetic lethal interaction between p300 inhibition and platinum-induced DNA damage, offering a targeted strategy to overcome chemoresistance.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"538-562"},"PeriodicalIF":7.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146124586","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

It takes two to cleave: the logic of cluster assistance. 分裂需要两个因素：集群援助的逻辑。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-04-01 DOI: 10.1101/gad.353586.125

Owen Sanborn, Daniel Cifuentes

引用次数: 0

A brain-specific microRNA, miR-1000, regulates lipid homeostasis via neuropeptide-like precursor 1 in Drosophila melanogaster. 一种脑特异性microRNA miR-1000通过神经肽样前体1调节黑腹果蝇的脂质稳态。

IF 7.4 1区生物学

Genes & development Pub Date : 2026-04-01 DOI: 10.1101/gad.353195.125

Pushpa Verma, Pruthvi Gowda, Nika N Danial, David Van Vactor

引用次数: 0