Genes & development最新文献_第3页

A cell type-specific surveillance complex represses cryptic promoters during differentiation in an adult stem cell lineage 细胞类型特异性监视复合物在成体干细胞谱系分化过程中抑制隐式启动子

IF 10.5 1区生物学

Genes & development Pub Date : 2025-08-06 DOI: 10.1101/gad.352747.125

Neuza R. Matias, Lorenzo Gallicchio, Dan Lu, Jongmin J. Kim, Julian Perez, Angela M. Detweiler, Chenggang Lu, Benjamin Bolival, Margaret T. Fuller

{"title":"A cell type-specific surveillance complex represses cryptic promoters during differentiation in an adult stem cell lineage","authors":"Neuza R. Matias, Lorenzo Gallicchio, Dan Lu, Jongmin J. Kim, Julian Perez, Angela M. Detweiler, Chenggang Lu, Benjamin Bolival, Margaret T. Fuller","doi":"10.1101/gad.352747.125","DOIUrl":"https://doi.org/10.1101/gad.352747.125","url":null,"abstract":"Regulators of chromatin accessibility play key roles in cell fate transitions, triggering the onset of novel transcription programs as cells differentiate. In the Drosophila male germline stem cell lineage, tMAC, a master regulator of spermatocyte differentiation that binds thousands of loci, is required for local opening of chromatin, allowing activation of spermatocyte-specific promoters. Here we show that a cell type-specific surveillance system involving the multiple zinc finger protein Kmg and the pipsqueak domain protein Dany dampens transcriptional output from weak tMAC-dependent promoters and counteracts tMAC binding at thousands of additional cryptic promoters, thus preventing massive expression of aberrant protein-coding transcripts. ChIP-seq showed Kmg enriched at the tMAC-bound promoters that it repressed, consistent with direct action. In contrast, Kmg and Dany did not repress highly expressed tMAC-dependent genes, where they colocalized with their binding partner, the chromatin remodeler Mi-2 (NuRD), along the transcribed regions rather than at the promoter. We discuss a model where Kmg, together with Dany and Mi-2, dampens expression from weak or ectopic promoters while allowing robust transcription from highly expressed Aly-dependent genes.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"1 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792301","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

MYOD represses gene expression from non-E-box motifs MYOD抑制非e -box基序的基因表达

IF 10.5 1区生物学

Genes & development Pub Date : 2025-08-06 DOI: 10.1101/gad.352708.125

Chiara Nicoletti, Jimmy Massenet, Andreas P. Pintado-Urbanc, Leah J. Connor, Monica Nicolau, Swetha Sundar, Mingzhi Xu, Anthony Schmitt, Wenxin Zhang, Zesen Fang, Tsz Ching Indigo Chan, Yu Xin Wang, Stephen J. Tapscott, Tom H. Cheung, Matthew D. Simon, Luca Caputo, Pier Lorenzo Puri

{"title":"MYOD represses gene expression from non-E-box motifs","authors":"Chiara Nicoletti, Jimmy Massenet, Andreas P. Pintado-Urbanc, Leah J. Connor, Monica Nicolau, Swetha Sundar, Mingzhi Xu, Anthony Schmitt, Wenxin Zhang, Zesen Fang, Tsz Ching Indigo Chan, Yu Xin Wang, Stephen J. Tapscott, Tom H. Cheung, Matthew D. Simon, Luca Caputo, Pier Lorenzo Puri","doi":"10.1101/gad.352708.125","DOIUrl":"https://doi.org/10.1101/gad.352708.125","url":null,"abstract":"We report here on the identification of a previously unrecognized property of MYOD as a repressor of gene expression via E-box-independent chromatin binding during the process of somatic cell trans-differentiation into skeletal muscle. When ectopically expressed in proliferating human fibroblasts or endogenously induced in activated muscle stem cells (MuSCs), MYOD was detected at accessible regulatory elements of expressed genes, invariably leading to reduced chromatin accessibility and gene repression. At variance with conventional E-box-driven increased chromatin accessibility and H3K27 acetylation at previously silent loci of MYOD-activated genes, MYOD-mediated chromatin compaction and repression of transcription was associated with high occurrence of non-E-box motifs and did not lead to reduced levels of H3K27ac but coincided with reduced levels of H4 acetyl-methyl lysine modification (Kacme). Using MYOD mutants, we dissected the molecular mechanism of MYOD-mediated repression, whereby repression of mitogen-responsive and growth factor-responsive genes occurred via promoter binding, which requires a conserved domain within the first helix; conversely, repression of cell of origin/alternative lineage genes occurred via binding and decommissioning of distal regulatory elements such as superenhancers (SEs), required either the N-terminal activation domain or the two chromatin remodeling domains, and coincided with reduced strength of CTCF-mediated chromatin interactions. These data extend MYOD biological properties beyond the current dogma that restricts MYOD function to a monotone transcriptional activator. They also reveal an unprecedented functional versatility arising from alternative chromatin recruitment through E-box or non-E-box sequences, whereby genetic determinants dictate differential usage of MYOD functional domains.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"732 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792318","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

Aging is growing up: celebrating the latest research in aging and senescence biology 衰老正在成长：庆祝衰老和衰老生物学的最新研究

IF 10.5 1区生物学

Genes & development Pub Date : 2025-08-01 DOI: 10.1101/gad.353136.125

Andrew Dillin

引用次数: 0

Leukemia mutated proteins PHF6 and PHIP form a chromatin complex that represses acute myeloid leukemia stemness 白血病突变蛋白PHF6和PHIP形成染色质复合物，抑制急性髓系白血病的干细胞性

IF 10.5 1区生物学

Genes & development Pub Date : 2025-07-28 DOI: 10.1101/gad.352602.125

Aishwarya S. Pawar, Patrick Somers, Aleena Alex, Jason Grana, Victoria K. Feist, Subin S. George, Sapana S. Jalnapurkar, Charles Antony, Roman Verner, Sanese K. White-Brown, Mohit Khera, María Saraí Mendoza-Figueroa, Kathy Fange Liu, Jennifer J.D. Morrissette, Sandeep Gurbuxani, Vikram R. Paralkar

{"title":"Leukemia mutated proteins PHF6 and PHIP form a chromatin complex that represses acute myeloid leukemia stemness","authors":"Aishwarya S. Pawar, Patrick Somers, Aleena Alex, Jason Grana, Victoria K. Feist, Subin S. George, Sapana S. Jalnapurkar, Charles Antony, Roman Verner, Sanese K. White-Brown, Mohit Khera, María Saraí Mendoza-Figueroa, Kathy Fange Liu, Jennifer J.D. Morrissette, Sandeep Gurbuxani, Vikram R. Paralkar","doi":"10.1101/gad.352602.125","DOIUrl":"https://doi.org/10.1101/gad.352602.125","url":null,"abstract":"Myeloid leukemias are heterogeneous cancers with diverse mutations, sometimes in genes with unclear roles and unknown functional partners. PHF6 and PHIP are two poorly understood chromatin-binding proteins recurrently mutated in acute myeloid leukemia (AML). PHF6 mutations are associated with poorer outcomes, whereas PHIP was recently identified as the most common selective mutation in Black patients with AML. Here, we show that Phf6 knockout converts Flt3-ITD-driven mouse chronic myelomonocytic leukemia (CMML) into AML with reduced survival. Using cell line models, we show that PHF6 is a transcriptional repressor that suppresses a limited stemness gene network and that PHF6 missense mutations, classified by current clinical algorithms as variants of unknown significance, produce unstable or nonfunctional protein. We present multiple lines of evidence converging on a critical mechanistic connection between PHF6 and PHIP. We show that PHIP loss phenocopies PHF6 loss and that PHF6 requires PHIP to occupy chromatin and exert its downstream transcriptional program. Our work unifies PHF6 and PHIP, two disparate leukemia mutated proteins, into a common functional complex that suppresses AML stemness.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"62 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719698","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

Modeling and targeting general and chromosome-specific aneuploidy in cancer 癌症中一般和染色体特异性非整倍体的建模和靶向

IF 10.5 1区生物学

Genes & development Pub Date : 2025-07-28 DOI: 10.1101/gad.352766.125

Aleah Goldberg, Maria Trifas, Teresa Davoli

引用次数: 0

Structural basis of nucleosome recognition by the conserved Dsup and HMGN nucleosome-binding motif 保守的Dsup和HMGN核小体结合基序识别核小体的结构基础

IF 10.5 1区生物学

Genes & development Pub Date : 2025-07-28 DOI: 10.1101/gad.352720.125

Jaime Alegrio-Louro, Grisel Cruz-Becerra, George A. Kassavetis, James T. Kadonaga, Andres E. Leschziner

引用次数: 0

Lineage rewiring in lung adenocarcinoma via HNF4α and NKX2-1 dynamics 通过HNF4α和NKX2-1动力学的肺腺癌谱系重新布线

IF 10.5 1区生物学

Genes & development Pub Date : 2025-07-24 DOI: 10.1101/gad.353142.125

Alice Feng, Alena Yermalovich, Matthew Meyerson

引用次数: 0

Speed of life: tuning the ticktock of the segmentation clock 生活的速度：调整分割时钟的滴答声

IF 10.5 1区生物学

Genes & development Pub Date : 2025-07-17 DOI: 10.1101/gad.353096.125

Sally Lowell

引用次数: 0

A genome-wide, CRISPR-based screen reveals new requirements for translation initiation and ubiquitination in driving adipogenic fate change 基于crispr的全基因组筛选揭示了翻译起始和泛素化在驱动脂肪生成命运变化中的新要求

IF 10.5 1区生物学

Genes & development Pub Date : 2025-07-17 DOI: 10.1101/gad.352779.125

Rachel E. Turn, Keren I. Hilgendorf, Carl T. Johnson, Kyuho Han, Mohammad Ovais Aziz-Zanjani, Samuel Swails Bollinger, Pablo Domizi, Ran Cheng, Atefeh Rabiee, Yingdi Zhu, Zewen Jiang, Anushweta Asthana, Janos Demeter, Katrin J. Svensson, Michael C. Bassik, Peter K. Jackson

{"title":"A genome-wide, CRISPR-based screen reveals new requirements for translation initiation and ubiquitination in driving adipogenic fate change","authors":"Rachel E. Turn, Keren I. Hilgendorf, Carl T. Johnson, Kyuho Han, \u0000Mohammad Ovais Aziz-Zanjani, Samuel Swails Bollinger, Pablo Domizi, Ran Cheng, Atefeh Rabiee, Yingdi Zhu, Zewen Jiang, Anushweta Asthana, Janos Demeter, Katrin J. Svensson, Michael C. Bassik, Peter K. Jackson","doi":"10.1101/gad.352779.125","DOIUrl":"https://doi.org/10.1101/gad.352779.125","url":null,"abstract":"In response to excess nutrients, white adipose tissue expands by both generating new adipocytes and upregulating lipogenesis in existing adipocytes. Here, we performed a genome-wide functional CRISPR screen to identify regulators of adipogenesis in the mouse 3T3-L1 preadipocyte model. In this pooled screening strategy, we used FACS to isolate populations based on lipid content, gating for fluorescence intensity of lipophilic fluorescent BODIPY dye. Additionally, we categorized whether the gene functions primarily during mitotic clonal expansion, lipogenesis, or both. We found that translation initiation and ubiquitin-dependent protein stability regulators drive both adipogenic fate change and lipogenesis. We further supported these findings with proteomics, demonstrating that essential changes in protein reprogramming can drive or inhibit 3T3-L1 adipogenesis independent of transcription. Furthermore, we demonstrated that specific branches of the hypusination pathway, a conserved regulator of translation initiation, are critical for translating adipogenic inducers of mitotic clonal expansion and that the neddylation/ubiquitin pathway modulates insulin sensitivity during lipogenesis.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"73 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652094","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

Killing wisely: precision senolytics in the age of frailty 明智地杀戮：脆弱时代的精准老年学

IF 10.5 1区生物学

Genes & development Pub Date : 2025-07-15 DOI: 10.1101/gad.353134.125

Valentin J.A. Barthet, Scott W. Lowe

引用次数: 0