The effective proliferation and differentiation of trophoblast stem cells (TSCs) is indispensable for the development of the placenta, which is the key to maintaining normal fetal growth during pregnancy. Kruppel-like factor 5 (Klf5) is implicated in the activation of pluripotency gene expression in embryonic stem cells (ESCs), yet its function in TSCs is poorly understood. Here, we showed that Klf5 knockdown resulted in the downregulation of core TSC-specific genes, consequently causing rapid differentiation of TSCs. Consistently, Klf5-depleted embryos lost the ability to establish TSCs in vitro. At the molecular level, Klf5 preferentially occupied the proximal promoter regions and maintained an open chromatin architecture of key TSC-specific genes. Deprivation of Klf5 impaired the enrichment of p300, a major histone acetyl transferase of H3 lysine 27 acetylation (H3K27ac), and further reduced the occupancy of H3K27ac at promoter regions, leading to decreased transcriptional activity of TSC pluripotency genes. Thus, our findings highlight a novel mechanism of Klf5 in regulating the self-renewal and differentiation of TSCs and provide a reference for understanding placental development and improving pregnancy rates.
{"title":"The transcriptional activator Klf5 recruits p300-mediated H3K27ac for maintaining trophoblast stem cell pluripotency.","authors":"Chengli Dou, Linhui Wu, Jingjing Zhang, Hainan He, Tian Xu, Zhisheng Yu, Peng Su, Xia Zhang, Junling Wang, Yi-Liang Miao, Jilong Zhou","doi":"10.1093/jmcb/mjad045","DOIUrl":"10.1093/jmcb/mjad045","url":null,"abstract":"<p><p>The effective proliferation and differentiation of trophoblast stem cells (TSCs) is indispensable for the development of the placenta, which is the key to maintaining normal fetal growth during pregnancy. Kruppel-like factor 5 (Klf5) is implicated in the activation of pluripotency gene expression in embryonic stem cells (ESCs), yet its function in TSCs is poorly understood. Here, we showed that Klf5 knockdown resulted in the downregulation of core TSC-specific genes, consequently causing rapid differentiation of TSCs. Consistently, Klf5-depleted embryos lost the ability to establish TSCs in vitro. At the molecular level, Klf5 preferentially occupied the proximal promoter regions and maintained an open chromatin architecture of key TSC-specific genes. Deprivation of Klf5 impaired the enrichment of p300, a major histone acetyl transferase of H3 lysine 27 acetylation (H3K27ac), and further reduced the occupancy of H3K27ac at promoter regions, leading to decreased transcriptional activity of TSC pluripotency genes. Thus, our findings highlight a novel mechanism of Klf5 in regulating the self-renewal and differentiation of TSCs and provide a reference for understanding placental development and improving pregnancy rates.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10768793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9927286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Honglu Liu, Huanyi Fu, Chunhong Yu, Na Zhang, Canhua Huang, Lu Lv, Chunhong Hu, Fang Chen, Zhiqiang Xiao, Zhuohua Zhang, Huasong Lu, Kai Yuan
Lesions on the DNA template can impact transcription via distinct regulatory pathways. Ionizing radiation (IR) as the mainstay modality for many malignancies elicits most of the cytotoxicity by inducing a variety of DNA damages in the genome. How the IR treatment alters the transcription cycle and whether it contributes to the development of radioresistance remain poorly understood. Here, we report an increase in the paused RNA polymerase II (RNAPII), as indicated by the phosphorylation at serine 5 residue of its C-terminal domain, in recurrent nasopharyngeal carcinoma (NPC) patient samples after IR treatment and cultured NPC cells developing IR resistance. Reducing the pool of paused RNAPII by either inhibiting TFIIH-associated CDK7 or stimulating the positive transcription elongation factor b, a CDK9-CycT1 heterodimer, attenuates IR resistance of NPC cells. Interestingly, the poly(ADP-ribosyl)ation of CycT1, which disrupts its phase separation, is elevated in the IR-resistant cells. Mutation of the major poly(ADP-ribosyl)ation sites of CycT1 decreases RNAPII pausing and restores IR sensitivity. Genome-wide chromatin immunoprecipitation followed by sequencing analyses reveal that several genes involved in radiation response and cell cycle control are subject to the regulation imposed by the paused RNAPII. Particularly, we identify the NIMA-related kinase NEK7 under such regulation as a new radioresistance factor, whose downregulation results in the increased chromosome instability, enabling the development of IR resistance. Overall, our results highlight a novel link between the alteration in the transcription cycle and the acquisition of IR resistance, opening up new opportunities to increase the efficacy of radiotherapy and thwart radioresistance in NPC.
DNA 模板上的损伤可通过不同的调控途径影响转录。电离辐射(IR)是治疗许多恶性肿瘤的主要方法,它通过诱导基因组中的各种 DNA 损伤产生大部分细胞毒性。人们对红外治疗如何改变转录周期以及它是否会导致放射抗药性的产生仍然知之甚少。在这里,我们报告了在接受红外线治疗后的复发性鼻咽癌(NPC)患者样本中,暂停的RNA聚合酶II(RNAPII)增加的情况,其C端结构域丝氨酸5残基的磷酸化表明了这一点。通过抑制与 TFIIH 相关的 CDK7 或刺激 CDK9-CycT1 异源二聚体中的正转录延伸因子 b 来减少暂停的 RNAPII 池,可减轻鼻咽癌细胞的红外抗性。有趣的是,在耐红外细胞中,CycT1 的多(ADP-核糖基)硫酸化会破坏其相分离。突变 CycT1 的主要多聚(ADP-核糖基)连接位点可减少 RNAPII 的暂停并恢复对 IR 的敏感性。全基因组染色质免疫沉淀和测序分析表明,一些参与辐射响应和细胞周期控制的基因受到暂停的 RNAPII 的调控。特别是,我们发现受这种调控的 NIMA 相关激酶 NEK7 是一种新的放射抗性因子,它的下调会导致染色体不稳定性增加,从而产生红外抗性。总之,我们的研究结果突显了转录周期的改变与获得红外耐药性之间的新联系,为提高放疗疗效和挫败鼻咽癌的放射耐药性开辟了新的机遇。
{"title":"Transcriptional pausing induced by ionizing radiation enables the acquisition of radioresistance in nasopharyngeal carcinoma.","authors":"Honglu Liu, Huanyi Fu, Chunhong Yu, Na Zhang, Canhua Huang, Lu Lv, Chunhong Hu, Fang Chen, Zhiqiang Xiao, Zhuohua Zhang, Huasong Lu, Kai Yuan","doi":"10.1093/jmcb/mjad044","DOIUrl":"10.1093/jmcb/mjad044","url":null,"abstract":"<p><p>Lesions on the DNA template can impact transcription via distinct regulatory pathways. Ionizing radiation (IR) as the mainstay modality for many malignancies elicits most of the cytotoxicity by inducing a variety of DNA damages in the genome. How the IR treatment alters the transcription cycle and whether it contributes to the development of radioresistance remain poorly understood. Here, we report an increase in the paused RNA polymerase II (RNAPII), as indicated by the phosphorylation at serine 5 residue of its C-terminal domain, in recurrent nasopharyngeal carcinoma (NPC) patient samples after IR treatment and cultured NPC cells developing IR resistance. Reducing the pool of paused RNAPII by either inhibiting TFIIH-associated CDK7 or stimulating the positive transcription elongation factor b, a CDK9-CycT1 heterodimer, attenuates IR resistance of NPC cells. Interestingly, the poly(ADP-ribosyl)ation of CycT1, which disrupts its phase separation, is elevated in the IR-resistant cells. Mutation of the major poly(ADP-ribosyl)ation sites of CycT1 decreases RNAPII pausing and restores IR sensitivity. Genome-wide chromatin immunoprecipitation followed by sequencing analyses reveal that several genes involved in radiation response and cell cycle control are subject to the regulation imposed by the paused RNAPII. Particularly, we identify the NIMA-related kinase NEK7 under such regulation as a new radioresistance factor, whose downregulation results in the increased chromosome instability, enabling the development of IR resistance. Overall, our results highlight a novel link between the alteration in the transcription cycle and the acquisition of IR resistance, opening up new opportunities to increase the efficacy of radiotherapy and thwart radioresistance in NPC.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10960568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9746355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mono-ADP-ribosylation (MARylation) is a post-translational modification that regulates a variety of biological processes, including DNA damage repair, cell proliferation, metabolism, and stress and immune responses. In mammals, MARylation is mainly catalyzed by ADP-ribosyltransferases (ARTs), which consist of two groups: ART cholera toxin-like (ARTCs) and ART diphtheria toxin-like (ARTDs, also known as PARPs). The human ARTC (hARTC) family is composed of four members: two active mono-ADP-ARTs (hARTC1 and hARTC5) and two enzymatically inactive enzymes (hARTC3 and hARTC4). In this study, we systematically examined the homology, expression, and localization pattern of the hARTC family, with a particular focus on hARTC1. Our results showed that hARTC3 interacted with hARTC1 and promoted the enzymatic activity of hARTC1 by stabilizing hARTC1. We also identified vesicle-associated membrane protein-associated protein B (VAPB) as a new target of hARTC1 and pinpointed Arg50 of VAPB as the ADP-ribosylation site. Furthermore, we demonstrated that knockdown of hARTC1 impaired intracellular calcium homeostasis, highlighting the functional importance of hARTC1-mediated VAPB Arg50 ADP-ribosylation in regulating calcium homeostasis. In summary, our study identified a new target of hARTC1 in the endoplasmic reticulum and suggested that ARTC1 plays a role in regulating calcium signaling.
{"title":"ARTC1-mediated VAPB ADP-ribosylation regulates calcium homeostasis.","authors":"Xueyao Ma, Mengyuan Li, Yi Liu, Xuefang Zhang, Xiaoyun Yang, Yun Wang, Yipeng Li, Jiayue Wang, Xiuhua Liu, Zhenzhen Yan, Xiaochun Yu, Chen Wu","doi":"10.1093/jmcb/mjad043","DOIUrl":"10.1093/jmcb/mjad043","url":null,"abstract":"<p><p>Mono-ADP-ribosylation (MARylation) is a post-translational modification that regulates a variety of biological processes, including DNA damage repair, cell proliferation, metabolism, and stress and immune responses. In mammals, MARylation is mainly catalyzed by ADP-ribosyltransferases (ARTs), which consist of two groups: ART cholera toxin-like (ARTCs) and ART diphtheria toxin-like (ARTDs, also known as PARPs). The human ARTC (hARTC) family is composed of four members: two active mono-ADP-ARTs (hARTC1 and hARTC5) and two enzymatically inactive enzymes (hARTC3 and hARTC4). In this study, we systematically examined the homology, expression, and localization pattern of the hARTC family, with a particular focus on hARTC1. Our results showed that hARTC3 interacted with hARTC1 and promoted the enzymatic activity of hARTC1 by stabilizing hARTC1. We also identified vesicle-associated membrane protein-associated protein B (VAPB) as a new target of hARTC1 and pinpointed Arg50 of VAPB as the ADP-ribosylation site. Furthermore, we demonstrated that knockdown of hARTC1 impaired intracellular calcium homeostasis, highlighting the functional importance of hARTC1-mediated VAPB Arg50 ADP-ribosylation in regulating calcium homeostasis. In summary, our study identified a new target of hARTC1 in the endoplasmic reticulum and suggested that ARTC1 plays a role in regulating calcium signaling.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10928986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10051793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To facilitate survival, replication, and dissemination, the intracellular pathogen Legionella pneumophila relies on its unique type IVB secretion system (T4SS) to deliver over 330 effectors to hijack host cell pathways in a spatiotemporal manner. The effectors and their host targets are largely unexplored due to their low sequence identity to the known proteins and functional redundancy. The T4SS effector SidN (Lpg1083) is secreted into host cells during the late infection period. However, to the best of our knowledge, the molecular characterization of SidN has not been studied. Herein, we identified SidN as a nuclear envelope-localized effector. Its structure adopts a novel fold, and the N-terminal domain is crucial for its specific subcellular localization. Furthermore, we found that SidN is transported by eukaryotic karyopherin Importin-13 into the nucleus, where it attaches to the N-terminal region of Lamin-B2 to interfere with the integrity of the nuclear envelope, causing nuclear membrane disruption and eventually cell death. Our work provides new insights into the structure and function of an L. pneumophila effector protein, and suggests a potential strategy utilized by the pathogen to promote host cell death and then escape from the host for secondary infection.
{"title":"The bacterial effector SidN/Lpg1083 promotes cell death by targeting Lamin-B2.","authors":"Jiajia Gao, Wenwen Xu, Feng Tang, Minrui Xu, Qin Zhou, Xingyuan Yang, Nannan Zhang, Jinming Ma, Qi Yang, Xiaofang Chen, Ximing Qin, Honghua Ge","doi":"10.1093/jmcb/mjad036","DOIUrl":"10.1093/jmcb/mjad036","url":null,"abstract":"<p><p>To facilitate survival, replication, and dissemination, the intracellular pathogen Legionella pneumophila relies on its unique type IVB secretion system (T4SS) to deliver over 330 effectors to hijack host cell pathways in a spatiotemporal manner. The effectors and their host targets are largely unexplored due to their low sequence identity to the known proteins and functional redundancy. The T4SS effector SidN (Lpg1083) is secreted into host cells during the late infection period. However, to the best of our knowledge, the molecular characterization of SidN has not been studied. Herein, we identified SidN as a nuclear envelope-localized effector. Its structure adopts a novel fold, and the N-terminal domain is crucial for its specific subcellular localization. Furthermore, we found that SidN is transported by eukaryotic karyopherin Importin-13 into the nucleus, where it attaches to the N-terminal region of Lamin-B2 to interfere with the integrity of the nuclear envelope, causing nuclear membrane disruption and eventually cell death. Our work provides new insights into the structure and function of an L. pneumophila effector protein, and suggests a potential strategy utilized by the pathogen to promote host cell death and then escape from the host for secondary infection.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10729856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9547765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Biological functions and applications of circRNAs-next generation of RNA-based therapy.","authors":"Meiling Sun, Yun Yang","doi":"10.1093/jmcb/mjad031","DOIUrl":"10.1093/jmcb/mjad031","url":null,"abstract":"","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10708935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9468924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Effective therapy of the small-molecule cocktail 5SM on adult rat heart after ischemia-reperfusion injury.","authors":"Lixia Zheng, Yuanyuan Chen, Zhengyuan Wu, Xiaojun Zhu, Jing-Wei Xiong","doi":"10.1093/jmcb/mjad034","DOIUrl":"10.1093/jmcb/mjad034","url":null,"abstract":"","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10701712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9606878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hairong Yu, Haoyong Yu, Rong Zhang, Danfeng Peng, Dandan Yan, Yunjuan Gu, Yuqian Bao, Weiping Jia, Hong Zhang, Cheng Hu
A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause. Here, we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes. We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing (WES) data available for 146 of these patients. The coverage of targeted gene panel sequencing was significantly higher than that of WES. The diagnostic yield in patients sequenced by the panel was 32.9% with subsequent WES leading to three additional diagnoses with two novel genes. In total, 178 variants in 83 genes were detected in 146 patients by targeted sequencing. Three of the 178 variants were missed by WES, although the WES-only approach had a similar diagnostic yield. For the 335 samples only receiving targeted sequencing, the diagnostic yield was 32.2%. In conclusion, taking into account the lower costs, shorter turnaround time, and higher quality of data, targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES. Therefore, this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.
{"title":"Targeted gene panel provides advantages over whole-exome sequencing for diagnosing obesity and diabetes mellitus.","authors":"Hairong Yu, Haoyong Yu, Rong Zhang, Danfeng Peng, Dandan Yan, Yunjuan Gu, Yuqian Bao, Weiping Jia, Hong Zhang, Cheng Hu","doi":"10.1093/jmcb/mjad040","DOIUrl":"10.1093/jmcb/mjad040","url":null,"abstract":"<p><p>A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause. Here, we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes. We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing (WES) data available for 146 of these patients. The coverage of targeted gene panel sequencing was significantly higher than that of WES. The diagnostic yield in patients sequenced by the panel was 32.9% with subsequent WES leading to three additional diagnoses with two novel genes. In total, 178 variants in 83 genes were detected in 146 patients by targeted sequencing. Three of the 178 variants were missed by WES, although the WES-only approach had a similar diagnostic yield. For the 335 samples only receiving targeted sequencing, the diagnostic yield was 32.2%. In conclusion, taking into account the lower costs, shorter turnaround time, and higher quality of data, targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES. Therefore, this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10847719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9697132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rufeng Xu, Kaiyuan Wang, Zhengjian Yao, Yan Zhang, Li Jin, Jing Pang, Yuncai Zhou, Kai Wang, Dechen Liu, Yaqin Zhang, Peng Sun, Fuqiang Wang, Xiaoai Chang, Tengli Liu, Shusen Wang, Yalin Zhang, Shuyong Lin, Cheng Hu, Yunxia Zhu, Xiao Han
Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and β-cell biology. However, whether BRSK2 is associated with human type 2 diabetes mellitus (T2DM) has not been determined. Here, we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population. BRSK2 protein levels are significantly elevated in β cells from T2DM patients and high-fat diet (HFD)-fed mice due to enhanced protein stability. Mice with inducible β-cell-specific Brsk2 knockout (βKO) exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions. Moreover, βKO mice are protected from HFD-induced hyperinsulinemia, obesity, insulin resistance, and glucose intolerance. Conversely, gain-of-function BRSK2 in mature β cells reversibly triggers hyperglycemia due to β-cell hypersecretion-coupled insulin resistance. Mechanistically, BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner. The enhanced basal insulin secretion drives insulin resistance and β-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 in β cells. These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay between β cells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.
{"title":"BRSK2 in pancreatic β cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes.","authors":"Rufeng Xu, Kaiyuan Wang, Zhengjian Yao, Yan Zhang, Li Jin, Jing Pang, Yuncai Zhou, Kai Wang, Dechen Liu, Yaqin Zhang, Peng Sun, Fuqiang Wang, Xiaoai Chang, Tengli Liu, Shusen Wang, Yalin Zhang, Shuyong Lin, Cheng Hu, Yunxia Zhu, Xiao Han","doi":"10.1093/jmcb/mjad033","DOIUrl":"10.1093/jmcb/mjad033","url":null,"abstract":"<p><p>Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and β-cell biology. However, whether BRSK2 is associated with human type 2 diabetes mellitus (T2DM) has not been determined. Here, we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population. BRSK2 protein levels are significantly elevated in β cells from T2DM patients and high-fat diet (HFD)-fed mice due to enhanced protein stability. Mice with inducible β-cell-specific Brsk2 knockout (βKO) exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions. Moreover, βKO mice are protected from HFD-induced hyperinsulinemia, obesity, insulin resistance, and glucose intolerance. Conversely, gain-of-function BRSK2 in mature β cells reversibly triggers hyperglycemia due to β-cell hypersecretion-coupled insulin resistance. Mechanistically, BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner. The enhanced basal insulin secretion drives insulin resistance and β-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 in β cells. These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay between β cells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10782904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9840654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The organized three-dimensional chromosome architecture in the cell nucleus provides scaffolding for precise regulation of gene expression. When the cell changes its identity in the cell-fate decision-making process, extensive rearrangements of chromosome structures occur accompanied by large-scale adaptations of gene expression, underscoring the importance of chromosome dynamics in shaping genome function. Over the last two decades, rapid development of experimental methods has provided unprecedented data to characterize the hierarchical structures and dynamic properties of chromosomes. In parallel, these enormous data offer valuable opportunities for developing quantitative computational models. Here, we review a variety of large-scale polymer models developed to investigate the structures and dynamics of chromosomes. Different from the underlying modeling strategies, these approaches can be classified into data-driven ('top-down') and physics-based ('bottom-up') categories. We discuss their contributions to offering valuable insights into the relationships among the structures, dynamics, and functions of chromosomes and propose the perspective of developing data integration approaches from different experimental technologies and multidisciplinary theoretical/simulation methods combined with different modeling strategies.
{"title":"Large-scale data-driven and physics-based models offer insights into the relationships among the structures, dynamics, and functions of chromosomes.","authors":"Cibo Feng, Jin Wang, Xiakun Chu","doi":"10.1093/jmcb/mjad042","DOIUrl":"10.1093/jmcb/mjad042","url":null,"abstract":"<p><p>The organized three-dimensional chromosome architecture in the cell nucleus provides scaffolding for precise regulation of gene expression. When the cell changes its identity in the cell-fate decision-making process, extensive rearrangements of chromosome structures occur accompanied by large-scale adaptations of gene expression, underscoring the importance of chromosome dynamics in shaping genome function. Over the last two decades, rapid development of experimental methods has provided unprecedented data to characterize the hierarchical structures and dynamic properties of chromosomes. In parallel, these enormous data offer valuable opportunities for developing quantitative computational models. Here, we review a variety of large-scale polymer models developed to investigate the structures and dynamics of chromosomes. Different from the underlying modeling strategies, these approaches can be classified into data-driven ('top-down') and physics-based ('bottom-up') categories. We discuss their contributions to offering valuable insights into the relationships among the structures, dynamics, and functions of chromosomes and propose the perspective of developing data integration approaches from different experimental technologies and multidisciplinary theoretical/simulation methods combined with different modeling strategies.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10782906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9742628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sara Omari, Hyemin Lee, Jieqiong Wang, Shelya X Zeng, Hua Lu
Coiled-coil domain containing 3 (CCDC3, also called Favine) is a highly conserved protein initially identified as a protein secreted from adipocytes and endothelial cells in the vascular system with endocrine-like functions. Recently, CCDC3 was also found to function as a nuclear tumor suppressor in breast cancers. Although it is still understudied, CCDC3, since its discovery, has been shown to play multiple roles in lipid metabolism, fatty liver, abdominal obesity, anti-inflammation, atherosclerosis, and cancer. This essay is thus composed to offer an overview of these extracellular endocrine-like and intracellular (nuclear) functions of CCDC3. We also discuss the possible underlying cellular and molecular mechanisms of CCDC3, the implications for clinical translation, and the remaining puzzles about this special molecule.
{"title":"Extracellular and intracellular functions of coiled-coil domain containing 3.","authors":"Sara Omari, Hyemin Lee, Jieqiong Wang, Shelya X Zeng, Hua Lu","doi":"10.1093/jmcb/mjad037","DOIUrl":"10.1093/jmcb/mjad037","url":null,"abstract":"<p><p>Coiled-coil domain containing 3 (CCDC3, also called Favine) is a highly conserved protein initially identified as a protein secreted from adipocytes and endothelial cells in the vascular system with endocrine-like functions. Recently, CCDC3 was also found to function as a nuclear tumor suppressor in breast cancers. Although it is still understudied, CCDC3, since its discovery, has been shown to play multiple roles in lipid metabolism, fatty liver, abdominal obesity, anti-inflammation, atherosclerosis, and cancer. This essay is thus composed to offer an overview of these extracellular endocrine-like and intracellular (nuclear) functions of CCDC3. We also discuss the possible underlying cellular and molecular mechanisms of CCDC3, the implications for clinical translation, and the remaining puzzles about this special molecule.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10849165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9933476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}