Genes & development最新文献

Glc7/PP1 triggers Paf1 complex dissociation from RNA polymerase II to enable transcription termination. Glc7/PP1触发Paf1复合物从RNA聚合酶II中分离，从而使转录终止。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-05-04 DOI: 10.1101/gad.353379.125

Sanchirmaa Namjilsuren, Karen M Arndt

{"title":"Glc7/PP1 triggers Paf1 complex dissociation from RNA polymerase II to enable transcription termination.","authors":"Sanchirmaa Namjilsuren, Karen M Arndt","doi":"10.1101/gad.353379.125","DOIUrl":"10.1101/gad.353379.125","url":null,"abstract":"The mechanisms that control the dynamic composition of RNAPII elongation complexes govern major transitions in the transcription cycle yet are poorly understood. Here, we show that the transcription elongation factor Spt5 determines elongation complex composition to promote productive elongation and the transition to termination. Using an unbiased genetic screen and genomic approaches in Saccharomyces cerevisiae, we provide evidence that dephosphorylation of the Spt5 C-terminal repeat domain (CTR) by Glc7/PP1 is required to dislodge the Paf1 complex (Paf1C) from RNAPII near the cleavage and polyadenylation site (CPS). Mutations in Paf1C or the Spt5 CTR that dissociate Paf1C from RNAPII bypass the requirement for two critical regulators of Glc7 in the cleavage and polyadenylation factor that promote Glc7 enrichment at the 3' ends of genes. Depletion of Glc7 causes aberrant retention of Paf1C past the CPS and a dramatic increase in readthrough transcription, which is fully suppressed by Paf1C mutations. Our results demonstrate that Paf1C retention antagonizes transcription termination and that Glc7-mediated restructuring of the RNAPII elongation complex to evict Paf1C at the CPS is a critical step in the transition from elongation to termination.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"699-716"},"PeriodicalIF":7.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13078362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147369286","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

Nested pediatric low-grade glioma cerebral organoid avatars reveal glutamatergic neuron stromal growth dependency. 嵌套儿童低级别胶质瘤脑类器官化身显示谷氨酸能神经元基质生长依赖性。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-05-04 DOI: 10.1101/gad.353336.125

Enquan Xu, Christina Zhang, Fausto J Rodriguez, Sonika Dahiya, Corina Anastasaki, David H Gutmann

引用次数: 0

Embryonic stem cell factors DPPA2/4 amplify active H3K4me3-H2AK119ub chromatin domains in non-small cell lung cancer. 胚胎干细胞因子DPPA2/4在非小细胞肺癌中扩增活性H3K4me3-H2AK119ub染色质结构域。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-05-04 DOI: 10.1101/gad.353102.125

Janith A Seneviratne, Clare L Crisp, Eleanor Glancy, Natalie Choy, Winnie Tan, Matthew Neve, Melanie Stammers, Tongtong Wang, Ruby Johnstone, Arshnoor Kaur, Katie A Fennell, Marian L Burr, Benjamin L Parker, Shabih Shakeel, Melanie A Eckersley-Maslin

{"title":"Embryonic stem cell factors DPPA2/4 amplify active H3K4me3-H2AK119ub chromatin domains in non-small cell lung cancer.","authors":"Janith A Seneviratne, Clare L Crisp, Eleanor Glancy, Natalie Choy, Winnie Tan, Matthew Neve, Melanie Stammers, Tongtong Wang, Ruby Johnstone, Arshnoor Kaur, Katie A Fennell, Marian L Burr, Benjamin L Parker, Shabih Shakeel, Melanie A Eckersley-Maslin","doi":"10.1101/gad.353102.125","DOIUrl":"10.1101/gad.353102.125","url":null,"abstract":"Embryonic regulators are often re-expressed in cancers; however, the functional and molecular significance of this is not always understood. The epigenetic priming factors developmental pluripotency-associated 2 and 4 (DPPA2/4) have crucial roles in early development and are implicated in cancer pathogenesis. We reveal that in non-small cell lung cancer (NSCLC), DPPA2/4 coexpression is associated with poorly differentiated tumors and impaired patient outcomes. Biochemically, human DPPA2/4 multimerize for their protein stability and enhanced nucleosome binding activity. In NSCLC cells, DPPA2/4 bind CG-rich sequences including promoters of developmental genes, Wnt signaling, and catabolic genes. Chromatin state modeling revealed that DPPA2/4 preferentially bind active H3K4me3 and H3K27ac domains that were intriguingly also enriched for PRC1 and its product, H2AK119ub, which was validated by H3K4me3-H2AK119ub sequential ChIP. Knockdown experiments revealed that DPPA2/4 were required to maintain RING1B and H2AK119ub at these domains. Surprisingly, despite the presence of PRC2.1, these regions lacked any detectable H3K27me3, suggesting an uncoupling between the recruitment of PRC2 to chromatin and its catalytic product. When exogenously overexpressed in NSCLC cells where they are not normally present, DPPA2/4 bind to and promote active chromatin states, resulting in an increase in in vivo xenograft tumor growth. Our results demonstrate how, in NSCLC cells, DPPA2/4 act as molecular amplifiers of active and poised chromatin. Together, this highlights how aberrant reactivation of embryonic factors in cancers may take on new functions, promoting tumorigenesis.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"756-776"},"PeriodicalIF":7.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13138344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147491111","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

Lights up on the embryonic dance: tools and applications of optogenetics in developmental biology. 胚胎之舞：光遗传学在发育生物学中的工具和应用。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-05-04 DOI: 10.1101/gad.353459.125

Yang Gao, Emily K Ho, Jared E Toettcher

引用次数: 0

Temporal loss of En1 during limb development causes distinct phenotypes. 肢体发育过程中En1的时间缺失导致不同的表型。

IF 7.7 1区生物学

Genes & development Pub Date : 2026-05-04 DOI: 10.1101/gad.353542.125

Alessa R Ringel, Natalia Benetti, Andreas Magg, Fabian Groll, Robert Schöpflin, Mira Kühnlein, Asita Carola Stiege, Ute Fischer, Lars Wittler, Laurence Game, Stephan Lorenz, George Young, Stefan Mundlos, Lila Allou

{"title":"Temporal loss of En1 during limb development causes distinct phenotypes.","authors":"Alessa R Ringel, Natalia Benetti, Andreas Magg, Fabian Groll, Robert Schöpflin, Mira Kühnlein, Asita Carola Stiege, Ute Fischer, Lars Wittler, Laurence Game, Stephan Lorenz, George Young, Stefan Mundlos, Lila Allou","doi":"10.1101/gad.353542.125","DOIUrl":"10.1101/gad.353542.125","url":null,"abstract":"The precise spatiotemporal regulation of developmental genes is required for proper organogenesis. Engrailed-1 (En1) is essential for dorsal-ventral patterning during mouse limb development from embryonic day 9.5 (E9.5) to E11.5. Previously, we identified the long noncoding RNA locus Maenli, which drives limb-specific En1 expression at E9.5. Here, we uncover two intergenic enhancer elements, LSEE1&2, that are essential for En1 expression at E10.5 and E11.5. We demonstrate that Maenli and LSEE1&2 coordinate two transcriptional waves of En1 expression that are essential for establishing dorsal-ventral limb identity. The early wave, controlled by Maenli, is required for ventral ectoderm and apical ectodermal ridge specification, while the late wave, associated with LSEE1&2, is critical for dorsal-ventral ectoderm specification in mouse limbs. Loss of Maenli versus LSEE1&2 results in distinct developmental phenotypes by altering the spatiotemporal expression of key genes governing axial patterning pathways. Our study underscores how temporal cis-regulatory elements modulate lineage specification and developmental patterning through shaping spatiotemporal gene function during development, representing potential candidates underpinning isolated subphenotypes.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"627-637"},"PeriodicalIF":7.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13138323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147689679","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 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 7.7 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":7.7,"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

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 7.7 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":7.7,"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

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 7.7 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":7.7,"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

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 7.7 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":7.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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 7.7 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":7.7,"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