SIN3A

LINE-1是逆转录转座子的主要分支，具有自主逆转录活性。尽管有潜在的遗传毒性，LINE-1在早期胚胎中是高度激活的。2023年8月17日，东南大学林承棋及罗卓娟共同通讯在Nature Cell Biology 在线发表题为“Young LINE-1 transposon 5′UTRs marked by  elongation factor ELL3 function as enhancers to regulate naïve pluripotency in embryonic stem cells”的研究论文，该研究展示了年轻LINE-1的一个子集，L1Md_Ts，被RNA聚合酶II延伸因子ELL3标记，并在小鼠胚胎干细胞中作为增强子起作用。ELL3缺失使L1Md_T的DNA羟甲基化酶TET1和共抑制因子SIN3A移除了，但增加了布罗莫结构域蛋白BRD4的富集，导致5hmC的缺失，H3K27ac的增加，以及L1Md_T附近基因的上调。具体来说，ELL3占据并抑制位于Akt3内的L1Md_T-based增强子，该增强子编码AKT通路的关键调节因子。ELL3是通过在naïve-primed过渡过程中抑制Akt3来适当激活ERK和有效关闭原始态多能性所必需的。该研究揭示了ELL3控制的年轻LINE-1亚群在转录调控和小鼠早期胚胎发育中的增强子功能。近一半的哺乳动物基因组由逆转录转座子组成。大多数逆转录转座子退化成先前入侵的化石记录。最近进化的长间隔核元素-1 (LINE-1)是目前哺乳动物中仍具有自主移动能力的逆转录转座子分支。在早期胚胎发育过程中广泛的表观遗传重编程导致LINE-1转录的短暂但强劲的上升。尽管LINE-1在着床前胚胎中具有突出的转录活性，但其逆转录频率却不成比例地低。在最近的研究中，LINE-1转录或转录本的调控功能已经超越了仅仅在宿主基因组中的繁殖。在小鼠早期胚胎中，LINE-1转录促进了整体染色质开放。LINE-1转录本被证明可以募集Nucleolin和KAP1来抑制双细胞(2C)胚胎特异性转录因子DUX，并调节基因组区室组织。LINE-1常位于或邻近宿主基因。然而，LINE-1是否在顺式中起调节基因表达的作用在很大程度上仍然不清楚。逆转录转座子在早期胚胎发生过程中受到严格的表观遗传控制。支架KAP1及其相关的组蛋白修饰因子如SETDB1可以通过Krüppel相关的盒锌指蛋白(KZFPs)以序列特异性的方式定向到包括衰老LINE-1在内的逆转录转座子上，确保染色质紧实和DNA无法被转录因子和RNA聚合酶接近。相反，在血清/白血病抑制因子(LIF)培养的小鼠胚胎干细胞(mESCs)中，处于转录许可状态的年轻LINE-1逃脱了KZFP介导的沉默，受到共抑制因子SIN3A和DNA羟化酶TET1的调节。发现TET1可以结合多个具有不同遗传和表观遗传特征的逆转录转座子类。Krüppel样锌指转录因子ZFP281可以将TET1和SIN3A募集到年轻的LINE-1亚群中。年轻的LINE-1表达在着床前达到峰值，而在这种naïve状态下调节年轻的LINE-1的因素在很大程度上仍然未知。文章模式图（图源自Nature Cell Biology）在血清/ LIF生长的mESCs中，作为1119赖氨酸-富白血病(ELL)家族成员的ELL3占据了增强子，并且是聚合酶II暂停在一组发育基因上所必需的。该研究证明了1Md_T的一个子集可以作为naïve状态下的增强子。ELL3位于L1Md_Ts的5 '非翻译区(UTRs)。ELL3的缺失导致基于L1Md_T增强子的超激活，以及其附近基因的上调。特别是，ELL3通过抑制位于其第一个内含子内的L1Md_T-based增强子的活性来抑制Akt3，从而调节RAF-ERK通路和naïve-primed转变。该研究表明，ELL3是在naïve-primed过渡期间有效沉默原始态多能性的关键因素，是通过调节L1Md_T-based增强子的活性来实现的。东南大学生命科学与技术学院林承棋教授和罗卓娟教授为该论文的共同通讯作者。东南大学生命科学与技术学院博士生孟思妍、刘晓旭、朱诗琪，及生物科学与医学工程学院的谢芃教授为该论文的共同第一作者。东南大学生命科学与技术学院方海同、方可为该论文的共同作者。东南大学生命科学与技术学院谢维教授、孙飞教授，及昆明理工大学的陈凯教授亦参与了本项研究。本研究获国家重点研发计划、国家自然科学基金、深圳市科技计划、云南省自然科学基金资助。文章来源“iNture”责编|文竞择校对|文竞择End往期精选围观历史性突破！不需卵子和精子就可以合成人类胚胎热文富豪用儿子血浆“回春”科学吗？Science：血液牛磺酸缺乏驱动衰老热文世界首例！35岁的她，通过机器人操刀移植的子宫，成功诞下宝宝热文为了避免心脏骤停，53岁的他成为“第一个”植入开创性除颤器的心脏病患者热文首次披露！175家生物制药公司的薪资数据：薪资中位数达20万美元点击“阅读原文”，了解更多~

LINE-1是逆转录转座子的主要分支，具有自主逆转录活性。尽管有潜在的遗传毒性，LINE-1在早期胚胎中是高度激活的。2023年8月17日，东南大学林承棋及罗卓娟共同通讯在Nature Cell Biology 在线发表题为“Young LINE-1 transposon 5′UTRs marked by  elongation factor ELL3 function as enhancers to regulate naïve pluripotency in embryonic stem cells”的研究论文，该研究展示了年轻LINE-1的一个子集，L1Md_Ts，被RNA聚合酶II延伸因子ELL3标记，并在小鼠胚胎干细胞中作为增强子起作用。ELL3缺失使L1Md_T的DNA羟甲基化酶TET1和共抑制因子SIN3A移除了，但增加了布罗莫结构域蛋白BRD4的富集，导致5hmC的缺失，H3K27ac的增加，以及L1Md_T附近基因的上调。具体来说，ELL3占据并抑制位于Akt3内的L1Md_T-based增强子，该增强子编码AKT通路的关键调节因子。ELL3是通过在naïve-primed过渡过程中抑制Akt3来适当激活ERK和有效关闭原始态多能性所必需的。该研究揭示了ELL3控制的年轻LINE-1亚群在转录调控和小鼠早期胚胎发育中的增强子功能。近一半的哺乳动物基因组由逆转录转座子组成。大多数逆转录转座子退化成先前入侵的化石记录。最近进化的长间隔核元素-1 (LINE-1)是目前哺乳动物中仍具有自主移动能力的逆转录转座子分支。在早期胚胎发育过程中广泛的表观遗传重编程导致LINE-1转录的短暂但强劲的上升。尽管LINE-1在着床前胚胎中具有突出的转录活性，但其逆转录频率却不成比例地低。在最近的研究中，LINE-1转录或转录本的调控功能已经超越了仅仅在宿主基因组中的繁殖。在小鼠早期胚胎中，LINE-1转录促进了整体染色质开放。LINE-1转录本被证明可以募集Nucleolin和KAP1来抑制双细胞(2C)胚胎特异性转录因子DUX，并调节基因组区室组织。LINE-1常位于或邻近宿主基因。然而，LINE-1是否在顺式中起调节基因表达的作用在很大程度上仍然不清楚。逆转录转座子在早期胚胎发生过程中受到严格的表观遗传控制。支架KAP1及其相关的组蛋白修饰因子如SETDB1可以通过Krüppel相关的盒锌指蛋白(KZFPs)以序列特异性的方式定向到包括衰老LINE-1在内的逆转录转座子上，确保染色质紧实和DNA无法被转录因子和RNA聚合酶接近。相反，在血清/白血病抑制因子(LIF)培养的小鼠胚胎干细胞(mESCs)中，处于转录许可状态的年轻LINE-1逃脱了KZFP介导的沉默，受到共抑制因子SIN3A和DNA羟化酶TET1的调节。发现TET1可以结合多个具有不同遗传和表观遗传特征的逆转录转座子类。Krüppel样锌指转录因子ZFP281可以将TET1和SIN3A募集到年轻的LINE-1亚群中。年轻的LINE-1表达在着床前达到峰值，而在这种naïve状态下调节年轻的LINE-1的因素在很大程度上仍然未知。文章模式图（图源自Nature Cell Biology）在血清/ LIF生长的mESCs中，作为1119赖氨酸-富白血病(ELL)家族成员的ELL3占据了增强子，并且是聚合酶II暂停在一组发育基因上所必需的。该研究证明了1Md_T的一个子集可以作为naïve状态下的增强子。ELL3位于L1Md_Ts的5 '非翻译区(UTRs)。ELL3的缺失导致基于L1Md_T增强子的超激活，以及其附近基因的上调。特别是，ELL3通过抑制位于其第一个内含子内的L1Md_T-based增强子的活性来抑制Akt3，从而调节RAF-ERK通路和naïve-primed转变。该研究表明，ELL3是在naïve-primed过渡期间有效沉默原始态多能性的关键因素，是通过调节L1Md_T-based增强子的活性来实现的。东南大学生命科学与技术学院林承棋教授和罗卓娟教授为该论文的共同通讯作者。东南大学生命科学与技术学院博士生孟思妍、刘晓旭、朱诗琪，及生物科学与医学工程学院的谢芃教授为该论文的共同第一作者。东南大学生命科学与技术学院方海同、方可为该论文的共同作者。东南大学生命科学与技术学院谢维教授、孙飞教授，及昆明理工大学的陈凯教授亦参与了本项研究。本研究获国家重点研发计划、国家自然科学基金、深圳市科技计划、云南省自然科学基金资助。文章来源“iNture”责编|文竞择校对|文竞择End往期精选围观历史性突破！不需卵子和精子就可以合成人类胚胎热文富豪用儿子血浆“回春”科学吗？Science：血液牛磺酸缺乏驱动衰老热文世界首例！35岁的她，通过机器人操刀移植的子宫，成功诞下宝宝热文为了避免心脏骤停，53岁的他成为“第一个”植入开创性除颤器的心脏病患者热文首次披露！175家生物制药公司的薪资数据：薪资中位数达20万美元点击“阅读原文”，了解更多~

A potential new Alzheimer's drug represses the harmful inflammatory response of the brain's immune cells, reducing disease pathology, preserving neurons and improving cognition in preclinical tests. Though drug developers have achieved some progress in treating Alzheimer's disease with medicines that reduce amyloid-beta protein, other problems of the disease including inflammation, continue unchecked. In a new study, scientists at The Picower Institute for Learning and Memory at MIT describe a candidate drug that in human cell cultures and Alzheimer's mouse models reduced inflammation and improved memory. The target of the new "A11" molecule is a genetic transcription factor called PU.1. Prior research has shown that amid Alzheimer's disease, PU.1 becomes an overzealous director of inflammatory gene expression in the brain's microglia immune cells. A11 suppresses this problematic PU.1 activity, the new research shows, by recruiting other proteins that repress the inflammatory genes PU.1 works to express. But because A11 concentrates mostly in the brain and does not reduce PU.1 levels, it does not appear to disrupt PU.1's other job, which is to ensure the production of a wide variety of blood cells. "Inflammation is a major component of Alzheimer's disease pathology that has been especially hard to treat," said study senior author Li-Huei Tsai, Picower Professor of Neuroscience at MIT and director of The Picower Institute and MIT's Aging Brain Initiative. "This preclinical study demonstrates that A11 reduces inflammation in human microglia-like cells as well as in multiple mouse models of Alzheimer's disease and significantly improves cognition in the mice. We believe A11 therefore merits further development and testing." Tsai and Elizabeta Gjoneska of the National Institutes of Health are co-corresponding authors of the study published in the Journal of Experimental Medicine. As a postdoc, Gjoneska co-led a 2015 study that implicated PU.1 as a regulator of errant microglia inflammation in a mouse model of Alzheimer's disease. That research was a collaboration between Tsai's lab and that of MIT Computer Science Professor Manolis Kellis, co-led by former postdoc Andreas Pfenning, now a faculty member at Carnegie Mellon University. Ever since then, Tsai has been seeking a safe way to restore PU.1 activity to healthier levels. The work described in the new paper, led by Picower Institute research scientist William Ralvenius, starts with experiments to further validate that PU.1 would be a therapeutically meaningful target. To do that the scientists compared gene expression in immune cells of postmortem brain samples from Alzheimer's patients and mouse models and matching non-Alzheimer's controls. The comparisons showed that Alzheimer's effects major changes in microglial gene expression and that an increase in PU.1 binding to inflammatory gene targets was a significant component of that change. Moreover, they showed that reducing PU.1 activity in a mouse model of Alzheimer's reduced inflammation and neurodegeneration, the death of neurons. Screening success Genetically knocking down PU.1 in the body is not a viable therapeutic strategy given its importance in normal healthy function. The team therefore screened more than 58,000 small molecules from libraries of FDA-approved drugs and novel chemicals to see if any could safely and significantly reduce key inflammation and Alzheimer's related genes regulated by by PU.1 in cell cultures. After several rounds of increasingly stringent screening, they narrowed the field down to six chemicals. A11 was by far the most potent among them. They tested the effects of A11 doses on the function of human microglia-like cells cultured from patient stem cells. When they exposed the microglia-like cells to immune molecules that typically trigger inflammation, cells dosed with A11 exhibited reduced expression and secretion of inflammatory cytokines and less of the cell body shape changes associated with microglia inflammatory responses. The cells also showed less accumulation of lipid molecules, another sign of inflammatory activation. Looking at gene expression patterns, the scientists observed that A11-treated cells exposed to inflammatory triggers behaved much like unperturbed microglia, suggesting that A11 helps prevent microglia from overreacting to inflammatory cues. Two more lab tests aimed at understanding how A11 exerts its effects revealed that it doesn't change PU.1 levels. Instead it counteracts PU.1 activity by recruiting several proteins including MECP2, HDAC1, SIN3A and DMNT3A, known to repress expression of its targets. Essentially amid Alzheimer's disease, A11 tamps down what PU.1 amps up. "A11 represents a first-in-class molecule that converts PU.1 from a transcriptional activator to a transcriptional repressor, resulting in a controlled state of microglial inflammation," the authors wrote. Mice in mazes Having established that A11 reduced inflammatory activity in microglia and determined how that happens, the team focused on whether it worked as a medicine in mouse models of Alzheimer's disease. Pharmacological tests indicated that A11 is readily cleared from tissues and is capable of reaching brain cells. Moreover, in healthy mice the chemical successfully crossed the blood-brain barrier and remained in brain cells much longer than anywhere else. Finally the team tested the effects of the drugs on Alzheimer's disease pathology and symptoms in three mouse strains that each model different aspects of Alzheimer's disease: CK-p25 mice (severe neurodegeneration), Tau P301S transgenic mice (tauopathy), and 5XFAD mice (amyloid pathology). Male and female CK-p25 mice dosed with A11 showed less inflammatory response among microglia and astrocyte cells and lost fewer neurons than untreated controls. TauP301S Tg mice responded similarly, also exhibiting a significant reduction of phosphorylated tau protein in the hippocampus region of the brain, which is an essential area for memory. In 5XFAD mice, amyloid was significantly reduced. The team subjected the Tau P301S Tg and CK-p25 mice to mazes designed to test their short-term working memory and longer-term learning. In both models and on both tests, A11-treated mice performed significantly better than untreated controls. For example, in the "Morris Water Maze," where mice have to learn the location of a submerged platform that allows them to rest, treated CK-p25 mice learned much faster than untreated ones. Much more testing needs to be done before A11 could become an approved medicine, Tsai said, but she noted that it could complement the new treatments that target amyloid. "Given that A11 acts via a distinct mechanism from existing AD therapeutics, A11 could be used alone or in combination with approved therapeutics to provide improved treatment options for neurodegenerative diseases," the authors concluded. In addition to Tsai, Gjoneska and Ralvenius, the paper's other authors are Alison E. Mungenast, Hannah Woolf, Margaret M. Huston, Tyler Z. Gillingham, Stephen K. Godin, Jay Penney, Hugh P. Cam, Fan Gao, Celia G. Fernandez, Barbara Czako, Yaima Lightfoot, William J. Ray, Adrian Beckmann, Alison M. Goate, Edoardo Marcora, Carmen Romero-Molina, Pinar Ayata, and Anne Schaefer. The Robert A. and Renee E. Belfer Family Foundation and the National Institutes of Health funded the research. Additional support came from The JPB Foundation and The Picower Institute for Learning and Memory, The Halis Family Foundation, Lester A. Gimpelson and Jay L. and Caroll Miller.