Pub Date : 2024-09-05DOI: 10.1016/j.celrep.2024.114710
Thomas Sevrin, Hiroaki Imoto, Sarah Robertson, Nora Rauch, Uscinnia Dyn'ko, Katerina Koubova, Kieran Wynne, Walter Kolch, Oleksii S Rukhlenko, Boris N Kholodenko
Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient- or tumor-specific variations, we constructed cell-line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I½ and type II RAFi) in inhibiting phospho-ERK (ppERK) and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.
{"title":"Cell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells.","authors":"Thomas Sevrin, Hiroaki Imoto, Sarah Robertson, Nora Rauch, Uscinnia Dyn'ko, Katerina Koubova, Kieran Wynne, Walter Kolch, Oleksii S Rukhlenko, Boris N Kholodenko","doi":"10.1016/j.celrep.2024.114710","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114710","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient- or tumor-specific variations, we constructed cell-line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I½ and type II RAFi) in inhibiting phospho-ERK (ppERK) and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143032","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}
Pub Date : 2024-09-04DOI: 10.1016/j.celrep.2024.114700
Matthew M Edwards, Ning Wang, Ido Sagi, Shay Kinreich, Nissim Benvenisty, Jeannine Gerhardt, Dieter Egli, Amnon Koren
Genomic imprinting involves differential DNA methylation and gene expression between homologous paternal and maternal loci. It remains unclear, however, whether DNA replication also shows parent-of-origin-specific patterns at imprinted or other genomic regions. Here, we investigate genome-wide asynchronous DNA replication utilizing uniparental human embryonic stem cells containing either maternal-only (parthenogenetic) or paternal-only (androgenetic) DNA. Four clusters of imprinted genes exhibited differential replication timing based on parent of origin, while the remainder of the genome, 99.82%, showed no significant replication asynchrony between parental origins. Active alleles in imprinted gene clusters replicated earlier than their inactive counterparts. At the Prader-Willi syndrome locus, replication asynchrony spanned virtually the entirety of S phase. Replication asynchrony was carried through differentiation to neuronal precursor cells in a manner consistent with gene expression. This study establishes asynchronous DNA replication as a hallmark of large imprinted gene clusters.
基因组印记涉及同源父系和母系基因座之间不同的 DNA 甲基化和基因表达。然而,DNA复制是否也会在印记或其他基因组区域显示出来源于父母的特异性模式,目前仍不清楚。在这里,我们利用含有纯母系(孤雌胚胎)或纯父系(雄性遗传)DNA的单亲人类胚胎干细胞研究了全基因组的非同步DNA复制。四个印记基因簇表现出基于亲本来源的不同复制时间,而基因组的其余部分(99.82%)在亲本来源之间没有表现出明显的复制不同步。印记基因簇中活性等位基因的复制时间早于非活性等位基因。在普拉德-威利综合征(Prader-Willi syndrome)基因座上,复制不同步现象几乎贯穿了整个 S 期。复制不同步与基因表达的方式一致,在神经元前体细胞的分化过程中也是如此。这项研究证实,DNA复制不同步是大型印记基因簇的一个特征。
{"title":"Parent-of-origin-specific DNA replication timing is confined to large imprinted regions.","authors":"Matthew M Edwards, Ning Wang, Ido Sagi, Shay Kinreich, Nissim Benvenisty, Jeannine Gerhardt, Dieter Egli, Amnon Koren","doi":"10.1016/j.celrep.2024.114700","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114700","url":null,"abstract":"<p><p>Genomic imprinting involves differential DNA methylation and gene expression between homologous paternal and maternal loci. It remains unclear, however, whether DNA replication also shows parent-of-origin-specific patterns at imprinted or other genomic regions. Here, we investigate genome-wide asynchronous DNA replication utilizing uniparental human embryonic stem cells containing either maternal-only (parthenogenetic) or paternal-only (androgenetic) DNA. Four clusters of imprinted genes exhibited differential replication timing based on parent of origin, while the remainder of the genome, 99.82%, showed no significant replication asynchrony between parental origins. Active alleles in imprinted gene clusters replicated earlier than their inactive counterparts. At the Prader-Willi syndrome locus, replication asynchrony spanned virtually the entirety of S phase. Replication asynchrony was carried through differentiation to neuronal precursor cells in a manner consistent with gene expression. This study establishes asynchronous DNA replication as a hallmark of large imprinted gene clusters.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139450","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}
Pub Date : 2024-09-04DOI: 10.1016/j.celrep.2024.114696
Nataliya E Yelina, Eftychios Frangedakis, Zhemin Wang, Tina B Schreier, Jenna Rever, Marta Tomaselli, Edith C F Forestier, Kumari Billakurthi, Sibo Ren, Yahui Bai, Julia Stewart-Wood, Jim Haseloff, Silin Zhong, Julian M Hibberd
Chloroplasts develop from undifferentiated plastids in response to light. In angiosperms, after the perception of light, the Elongated Hypocotyl 5 (HY5) transcription factor initiates photomorphogenesis, and two families of transcription factors known as GOLDEN2-LIKE (GLK) and GATA are considered master regulators of chloroplast development. In addition, the MIR171-targeted SCARECROW-LIKE GRAS transcription factors also impact chlorophyll biosynthesis. The extent to which these proteins carry out conserved roles in non-seed plants is not known. Using the model liverwort Marchantia polymorpha, we show that GLK controls chloroplast biogenesis, and HY5 shows a small conditional effect on chlorophyll content. Chromatin immunoprecipitation sequencing (ChIP-seq) revealed that MpGLK has a broader set of targets than has been reported in angiosperms. We also identified a functional GLK homolog in green algae. In summary, our data support the hypothesis that GLK carries out a conserved role relating to chloroplast biogenesis in land plants and green algae.
{"title":"Streamlined regulation of chloroplast development in the liverwort Marchantia polymorpha.","authors":"Nataliya E Yelina, Eftychios Frangedakis, Zhemin Wang, Tina B Schreier, Jenna Rever, Marta Tomaselli, Edith C F Forestier, Kumari Billakurthi, Sibo Ren, Yahui Bai, Julia Stewart-Wood, Jim Haseloff, Silin Zhong, Julian M Hibberd","doi":"10.1016/j.celrep.2024.114696","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114696","url":null,"abstract":"<p><p>Chloroplasts develop from undifferentiated plastids in response to light. In angiosperms, after the perception of light, the Elongated Hypocotyl 5 (HY5) transcription factor initiates photomorphogenesis, and two families of transcription factors known as GOLDEN2-LIKE (GLK) and GATA are considered master regulators of chloroplast development. In addition, the MIR171-targeted SCARECROW-LIKE GRAS transcription factors also impact chlorophyll biosynthesis. The extent to which these proteins carry out conserved roles in non-seed plants is not known. Using the model liverwort Marchantia polymorpha, we show that GLK controls chloroplast biogenesis, and HY5 shows a small conditional effect on chlorophyll content. Chromatin immunoprecipitation sequencing (ChIP-seq) revealed that MpGLK has a broader set of targets than has been reported in angiosperms. We also identified a functional GLK homolog in green algae. In summary, our data support the hypothesis that GLK carries out a conserved role relating to chloroplast biogenesis in land plants and green algae.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139452","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}
Pub Date : 2024-09-04DOI: 10.1016/j.celrep.2024.114693
Maximilian C Vonolfen, Fenja L Meyer Zu Altenschildesche, Hyuck-Jin Nam, Susanne Brodesser, Akos Gyenis, Jan Buellesbach, Geanette Lam, Carl S Thummel, Gilles Storelli
Nutrient digestion, absorption, and export must be coordinated in the gut to meet the nutritional needs of the organism. We used the Drosophila intestine to characterize the mechanisms that coordinate the fate of dietary lipids. We identified enterocytes specialized in absorbing and exporting lipids to peripheral organs. Distinct hepatocyte-like cells, called oenocytes, communicate with these enterocytes to adjust intestinal lipid storage and export. A single transcription factor, Drosophila hepatocyte nuclear factor 4 (dHNF4), supports this gut-liver axis. In enterocytes, dHNF4 maximizes dietary lipid export by preventing their sequestration in cytoplasmic lipid droplets. In oenocytes, dHNF4 promotes the expression of the insulin antagonist ImpL2 to activate Foxo and suppress lipid retention in enterocytes. Disruption of this switch between lipid storage and export is associated with intestinal inflammation, suggesting a lipidic origin for inflammatory bowel diseases. These studies establish dHNF4 as a central regulator of intestinal metabolism and inter-organ lipid trafficking.
{"title":"Drosophila HNF4 acts in distinct tissues to direct a switch between lipid storage and export in the gut.","authors":"Maximilian C Vonolfen, Fenja L Meyer Zu Altenschildesche, Hyuck-Jin Nam, Susanne Brodesser, Akos Gyenis, Jan Buellesbach, Geanette Lam, Carl S Thummel, Gilles Storelli","doi":"10.1016/j.celrep.2024.114693","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114693","url":null,"abstract":"<p><p>Nutrient digestion, absorption, and export must be coordinated in the gut to meet the nutritional needs of the organism. We used the Drosophila intestine to characterize the mechanisms that coordinate the fate of dietary lipids. We identified enterocytes specialized in absorbing and exporting lipids to peripheral organs. Distinct hepatocyte-like cells, called oenocytes, communicate with these enterocytes to adjust intestinal lipid storage and export. A single transcription factor, Drosophila hepatocyte nuclear factor 4 (dHNF4), supports this gut-liver axis. In enterocytes, dHNF4 maximizes dietary lipid export by preventing their sequestration in cytoplasmic lipid droplets. In oenocytes, dHNF4 promotes the expression of the insulin antagonist ImpL2 to activate Foxo and suppress lipid retention in enterocytes. Disruption of this switch between lipid storage and export is associated with intestinal inflammation, suggesting a lipidic origin for inflammatory bowel diseases. These studies establish dHNF4 as a central regulator of intestinal metabolism and inter-organ lipid trafficking.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139448","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}
Pub Date : 2024-09-04DOI: 10.1016/j.celrep.2024.114706
Richard Apps, Angélique Biancotto, Julián Candia, Yuri Kotliarov, Shira Perl, Foo Cheung, Rohit Farmer, Matthew P Mulè, Nicholas Rachmaninoff, Jinguo Chen, Andrew J Martins, Rongye Shi, Huizhi Zhou, Neha Bansal, Paula Schum, Matthew J Olnes, Pedro Milanez-Almeida, Kyu Lee Han, Brian Sellers, Mario Cortese, Thomas Hagan, Nadine Rouphael, Bali Pulendran, Lisa King, Jody Manischewitz, Surender Khurana, Hana Golding, Robbert G van der Most, Howard B Dickler, Ronald N Germain, Pamela L Schwartzberg, John S Tsang
To gain insight into how an adjuvant impacts vaccination responses, we use systems immunology to study human H5N1 influenza vaccination with or without the adjuvant AS03, longitudinally assessing 14 time points including multiple time points within the first day after prime and boost. We develop an unsupervised computational framework to discover high-dimensional response patterns, which uncover adjuvant- and immunogenicity-associated early response dynamics, including some that differ post prime versus boost. With or without adjuvant, some vaccine-induced transcriptional patterns persist to at least 100 days after initial vaccination. Single-cell profiling of surface proteins, transcriptomes, and chromatin accessibility implicates transcription factors in the erythroblast-transformation-specific (ETS) family as shaping these long-lasting signatures, primarily in classical monocytes but also in CD8+ naive-like T cells. These cell-type-specific signatures are elevated at baseline in high-antibody responders in an independent vaccination cohort, suggesting that antigen-agnostic baseline immune states can be modulated by vaccine antigens alone to enhance future responses.
{"title":"Acute and persistent responses after H5N1 vaccination in humans.","authors":"Richard Apps, Angélique Biancotto, Julián Candia, Yuri Kotliarov, Shira Perl, Foo Cheung, Rohit Farmer, Matthew P Mulè, Nicholas Rachmaninoff, Jinguo Chen, Andrew J Martins, Rongye Shi, Huizhi Zhou, Neha Bansal, Paula Schum, Matthew J Olnes, Pedro Milanez-Almeida, Kyu Lee Han, Brian Sellers, Mario Cortese, Thomas Hagan, Nadine Rouphael, Bali Pulendran, Lisa King, Jody Manischewitz, Surender Khurana, Hana Golding, Robbert G van der Most, Howard B Dickler, Ronald N Germain, Pamela L Schwartzberg, John S Tsang","doi":"10.1016/j.celrep.2024.114706","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114706","url":null,"abstract":"<p><p>To gain insight into how an adjuvant impacts vaccination responses, we use systems immunology to study human H5N1 influenza vaccination with or without the adjuvant AS03, longitudinally assessing 14 time points including multiple time points within the first day after prime and boost. We develop an unsupervised computational framework to discover high-dimensional response patterns, which uncover adjuvant- and immunogenicity-associated early response dynamics, including some that differ post prime versus boost. With or without adjuvant, some vaccine-induced transcriptional patterns persist to at least 100 days after initial vaccination. Single-cell profiling of surface proteins, transcriptomes, and chromatin accessibility implicates transcription factors in the erythroblast-transformation-specific (ETS) family as shaping these long-lasting signatures, primarily in classical monocytes but also in CD8<sup>+</sup> naive-like T cells. These cell-type-specific signatures are elevated at baseline in high-antibody responders in an independent vaccination cohort, suggesting that antigen-agnostic baseline immune states can be modulated by vaccine antigens alone to enhance future responses.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139446","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}
Pub Date : 2024-09-03DOI: 10.1016/j.celrep.2024.114748
Ching Ying Huang, Martin W Nicholson, Jyun Yuan Wang, Chien Yu Ting, Ming Heng Tsai, Yu Che Cheng, Chun Lin Liu, Darien Z H Chan, Yi Chan Lee, Ching Chuan Hsu, Yu Hung Hsu, Chiou Fong Yang, Cindy M C Chang, Shu Chian Ruan, Po Ju Lin, Jen Hao Lin, Li Lun Chen, Marvin L Hsieh, Yuan Yuan Cheng, Wan Tseng Hsu, Yi Ling Lin, Chien Hsiun Chen, Yu Hsiang Hsu, Ying Ta Wu, Timothy A Hacker, Joseph C Wu, Timothy J Kamp, Patrick C H Hsieh
{"title":"Population-based high-throughput toxicity screen of human iPSC-derived cardiomyocytes and neurons.","authors":"Ching Ying Huang, Martin W Nicholson, Jyun Yuan Wang, Chien Yu Ting, Ming Heng Tsai, Yu Che Cheng, Chun Lin Liu, Darien Z H Chan, Yi Chan Lee, Ching Chuan Hsu, Yu Hung Hsu, Chiou Fong Yang, Cindy M C Chang, Shu Chian Ruan, Po Ju Lin, Jen Hao Lin, Li Lun Chen, Marvin L Hsieh, Yuan Yuan Cheng, Wan Tseng Hsu, Yi Ling Lin, Chien Hsiun Chen, Yu Hsiang Hsu, Ying Ta Wu, Timothy A Hacker, Joseph C Wu, Timothy J Kamp, Patrick C H Hsieh","doi":"10.1016/j.celrep.2024.114748","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114748","url":null,"abstract":"","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139451","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}
The strategy of lowering cholesterol levels by promoting cholesterol excretion is still lacking, and few molecular targets act on multiple cholesterol metabolic processes. In this study, we find that Nogo-B deficiency/inhibition simultaneously promotes hepatic uptake of cholesterol and cholesterol excretion. Nogo-B deficiency decreases cholesterol levels by activating ATP-binding cassette transporters (ABCs), apolipoprotein E (ApoE), and low-density lipoprotein receptor (LDLR) expression. We discover that Nogo-B interacts with liver X receptor α (LXRα), and Nogo-B deficiency inhibits ubiquitination degradation of LXRα, thereby enhancing its function on cholesterol excretion. Decreased cellular cholesterol levels further activate SREBP2 and LDLR expression, thereby promoting hepatic uptake of cholesterol. Nogo-B inhibition decreases atherosclerotic plaques and cholesterol levels in mice, and Nogo-B levels are correlated to cholesterol levels in human plasma. In this study, Nogo-B deficiency/inhibition not only promotes hepatic uptake of blood cholesterol but also facilitates cholesterol excretion. This study reports a strategy to lower cholesterol levels by inhibiting Nogo-B expression to promote hepatic cholesterol uptake and cholesterol excretion.
{"title":"Nogo-B inhibition facilitates cholesterol metabolism to reduce hypercholesterolemia.","authors":"Chao Xue, Peng Zeng, Ke Gong, Qian Li, Zian Feng, Mengyao Wang, Shasha Chen, Yanfang Yang, Jiaqi Li, Shuang Zhang, Zequn Yin, Yingquan Liang, Tengteng Yan, Miao Yu, Ke Feng, Dan Zhao, Xiaoxiao Yang, Xia Zhang, Likun Ma, Yasuko Iwakiri, Liang Chen, Xiaoqiang Tang, Yuanli Chen, Houzao Chen, Yajun Duan","doi":"10.1016/j.celrep.2024.114691","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114691","url":null,"abstract":"<p><p>The strategy of lowering cholesterol levels by promoting cholesterol excretion is still lacking, and few molecular targets act on multiple cholesterol metabolic processes. In this study, we find that Nogo-B deficiency/inhibition simultaneously promotes hepatic uptake of cholesterol and cholesterol excretion. Nogo-B deficiency decreases cholesterol levels by activating ATP-binding cassette transporters (ABCs), apolipoprotein E (ApoE), and low-density lipoprotein receptor (LDLR) expression. We discover that Nogo-B interacts with liver X receptor α (LXRα), and Nogo-B deficiency inhibits ubiquitination degradation of LXRα, thereby enhancing its function on cholesterol excretion. Decreased cellular cholesterol levels further activate SREBP2 and LDLR expression, thereby promoting hepatic uptake of cholesterol. Nogo-B inhibition decreases atherosclerotic plaques and cholesterol levels in mice, and Nogo-B levels are correlated to cholesterol levels in human plasma. In this study, Nogo-B deficiency/inhibition not only promotes hepatic uptake of blood cholesterol but also facilitates cholesterol excretion. This study reports a strategy to lower cholesterol levels by inhibiting Nogo-B expression to promote hepatic cholesterol uptake and cholesterol excretion.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139449","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}
Pub Date : 2024-09-03DOI: 10.1016/j.celrep.2024.114749
Rafael Sandoval-Rodríguez, Jenifer Alejandra Parra-Reyes, Wenfei Han, Pavel E Rueda-Orozco, Isaac O Perez, Ivan E de Araujo, Luis A Tellez
{"title":"D1 and D2 neurons in the nucleus accumbens enable positive and negative control over sugar intake in mice.","authors":"Rafael Sandoval-Rodríguez, Jenifer Alejandra Parra-Reyes, Wenfei Han, Pavel E Rueda-Orozco, Isaac O Perez, Ivan E de Araujo, Luis A Tellez","doi":"10.1016/j.celrep.2024.114749","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114749","url":null,"abstract":"","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139447","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}
Pub Date : 2024-09-02DOI: 10.1016/j.celrep.2024.114698
Natalie A Trigg, Colin C Conine
Sperm small RNAs have emerged as important non-genetic contributors to embryogenesis and offspring health. A subset of sperm small RNAs is thought to be acquired during epididymal transit. However, the identity of the specific small RNAs transferred remains unclear. Here, we employ Cre/Lox genetics to generate germline- and epididymal-specific Dgcr8 knockout (KO) mice to investigate the dynamics of sperm microRNAs (miRNAs) and their functions post-fertilization. Testicular sperm from germline Dgcr8 KO mice has reduced levels of 116 miRNAs. Enthrallingly, following epididymal transit, the abundance of 72% of these miRNAs is restored. Conversely, sperm from epididymal Dgcr8 KO mice displayed reduced levels of 27 miRNAs. This loss of epididymal miRNAs in sperm was accompanied by transcriptomic changes in embryos fertilized by this sperm, which was rescued by microinjection of epididymal miRNAs. These findings ultimately demonstrate the acquisition of miRNAs from the soma by sperm during epididymal transit and their subsequent regulation of embryonic gene expression.
{"title":"Epididymal acquired sperm microRNAs modify post-fertilization embryonic gene expression.","authors":"Natalie A Trigg, Colin C Conine","doi":"10.1016/j.celrep.2024.114698","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114698","url":null,"abstract":"<p><p>Sperm small RNAs have emerged as important non-genetic contributors to embryogenesis and offspring health. A subset of sperm small RNAs is thought to be acquired during epididymal transit. However, the identity of the specific small RNAs transferred remains unclear. Here, we employ Cre/Lox genetics to generate germline- and epididymal-specific Dgcr8 knockout (KO) mice to investigate the dynamics of sperm microRNAs (miRNAs) and their functions post-fertilization. Testicular sperm from germline Dgcr8 KO mice has reduced levels of 116 miRNAs. Enthrallingly, following epididymal transit, the abundance of 72% of these miRNAs is restored. Conversely, sperm from epididymal Dgcr8 KO mice displayed reduced levels of 27 miRNAs. This loss of epididymal miRNAs in sperm was accompanied by transcriptomic changes in embryos fertilized by this sperm, which was rescued by microinjection of epididymal miRNAs. These findings ultimately demonstrate the acquisition of miRNAs from the soma by sperm during epididymal transit and their subsequent regulation of embryonic gene expression.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124957","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}
Pub Date : 2024-08-31DOI: 10.1016/j.celrep.2024.114676
Xiaochun Yang, Krishanu Bhowmick, Shuyun Rao, Xiyan Xiang, Kazufumi Ohshiro, Richard L Amdur, Md Imtaiyaz Hassan, Taj Mohammad, Keith Crandall, Paolo Cifani, Kirti Shetty, Scott K Lyons, Joseph R Merrill, Anil K Vegesna, Sahara John, Patricia S Latham, James M Crawford, Bibhuti Mishra, Srinivasan Dasarathy, Xin Wei Wang, Herbert Yu, Zhanwei Wang, Hai Huang, Adrian R Krainer, Lopa Mishra
Obesity and fatty liver diseases-metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)-affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2-/- and Aldh2-/-Sptbn1+/- mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor β (TGF-β) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (β2-spectrin) to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal SMAD3 signaling by targeting SPTBN1 with small interfering RNA (siRNA). Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model and, additionally, improves glucose handling in Aldh2-/- and Aldh2-/-Sptbn1+/- mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.
{"title":"Aldehydes alter TGF-β signaling and induce obesity and cancer.","authors":"Xiaochun Yang, Krishanu Bhowmick, Shuyun Rao, Xiyan Xiang, Kazufumi Ohshiro, Richard L Amdur, Md Imtaiyaz Hassan, Taj Mohammad, Keith Crandall, Paolo Cifani, Kirti Shetty, Scott K Lyons, Joseph R Merrill, Anil K Vegesna, Sahara John, Patricia S Latham, James M Crawford, Bibhuti Mishra, Srinivasan Dasarathy, Xin Wei Wang, Herbert Yu, Zhanwei Wang, Hai Huang, Adrian R Krainer, Lopa Mishra","doi":"10.1016/j.celrep.2024.114676","DOIUrl":"https://doi.org/10.1016/j.celrep.2024.114676","url":null,"abstract":"<p><p>Obesity and fatty liver diseases-metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)-affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2<sup>-/-</sup> and Aldh2<sup>-/-</sup>Sptbn1<sup>+/-</sup> mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor β (TGF-β) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (β2-spectrin) to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal SMAD3 signaling by targeting SPTBN1 with small interfering RNA (siRNA). Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model and, additionally, improves glucose handling in Aldh2<sup>-/-</sup> and Aldh2<sup>-/-</sup>Sptbn1<sup>+/-</sup> mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104751","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}