The Role of Dot1L in developing and postnatal heart
Dot1L 在发育和产后心脏中的作用
基本信息
- 批准号:8750576
- 负责人:
- 金额:$ 38.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-01 至 2018-07-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAccountingAddressAdultAdverse effectsApoptosisBlood VesselsCardiacCardiac MyocytesCardiomegalyCardiomyopathiesCardiovascular AbnormalitiesCell CycleCell Cycle RegulationCell NucleusCell SizeChIP-seqChromatinChromatin Remodeling FactorDataData AnalysesDefectDevelopmentDilated CardiomyopathyDockingDystrophinEmbryoEnzymesEpigenetic ProcessExhibitsFutureGene ExpressionGene Expression RegulationGenesGenetic TranscriptionGoalsHealthHeartHeart DiseasesHistone AcetylationHistone H3HistonesHyperplasiaIn VitroInjuryIntercalated discLengthLysineMediatingMethylationMethyltransferaseModificationMorphologyMusMuscle CellsNeonatalPathway interactionsPerinatalPhenotypePlayPloidiesPregnancyProliferatingProteinsRNA SplicingRegulationRoleSecondary toStagingStructureTestingTherapeuticTimeTissuesTranscriptional RegulationWorkcardiac regenerationcardiac repaircardiogenesiscdc Genescofactorcongenital heart disorderembryonic stem cellgenome-wideheart functionhistone modificationin vivoinhibitor/antagonistinsightinterestleukemiamutantnew therapeutic targetpostnatalprogramsregenerative therapyresearch studytelomeretherapy developmenttranscription factortranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant): Regulation of gene transcription is key to understanding mechanisms underlying heart development, congenital heart disease, and developing therapies for heart regeneration post injury. Epigenetic modifications are key modulators of the transcriptional landscape, and as such, enzymes which catalyze these modifications have become a subject of great interest. In particular, histone modifications are thought to play key roles in multiple aspects of gene regulation, including mediating interactions with chromatin remodeling factors, docking of general or specific tissue specific transcription factors or cofactors, and perhaps mediating splicing. Histone acetylation and deacteylation have been intensely studied. More recently, histone methylation has come under scrutiny, and greater understanding of the role of specific methylation marks has emerged. The histone methylation mark histone H3 lysine 79 (H3K79), is uniquely catalyzed by the lysine methyltransferase, DOT1L. Multiple lines of evidence suggest critical and specific roles for DOT1L during cardiogenesis and in postnatal heart. DOT1L is highly expressed in the heart throughout development, and global ablation of Dot1L results in mid-gestation lethality with multiple cardiovascular abnormalities. Ablation of Dot1L in cardiomyocytes at mid-gestation with αMHC-cre results in cardiomyopathy in adult heart, accounted for in part by perturbation of dystrophin gene expression. Evidence from cardiomyocyte differentiation of mouse embryonic stem cells indicated that DOT1L plays a critical role at earliest stages of cardiomyocyte differentiation, yet no in vivo studies have addressed this issue. Accordingly, in preliminary studies, we have ablated Dot1L at E7.5 utilizing xMLCcre, and found that mutants exhibited cardiomyocyte hyperplasia, dying in the early postnatal period. Preliminary studies ablating Dot1L in perinatal mouse cardiomyocyte cultures demonstrated an ongoing requirement for Dot1L to regulate cardiomyocyte cell cycle. Preliminary studies have demonstrated enrichment of H3K79 methyl marks at cardiac gene loci in neonatal and adult myocytes. Together, these observations have led to our hypothesis that Dot1L is required in cardiomyocytes at embryonic, neonatal and adult stages for cardiomyocyte cell cycle regulation and progressive differentiation of cardiomyocytes. To test this hypothesis, our Specific Aims are: 1) To characterize the cardiac phenotype of early cardiomyocyte-specific Dot1L mutants. 2) To identify genes directly regulated, positively or negatively, by DOT1L mediated-H3K79 methylation in vivo. 3) To examine the requirement for Dot1L in postnatal and adult heart. Results of these studies will give mechanistic insight into the role of DOT1L in cardiomyocytes throughout distinct developmental stages and in postnatal and adult heart. Importantly, these studies promise to give insights into mechanisms by which epigenetic modifications regulate cardiomyocyte cell cycle, and are therefore likely to suggest therapeutic approaches for cardiac repair in both developing and adult heart. DOT1L inhibitors are currently being tested for treatment of MLL-associated leukemias, therefore our studies will be informative as to potential cardiac side effects of these inhibitors. Our studies will also address the future potential of DOT1L inhibitors
for cardiac regenerative therapies.
描述(由申请人提供):基因转录的调控是理解心脏发育、先天性心脏病和开发损伤后心脏再生疗法的关键。表观遗传修饰是转录景观的关键调节剂,因此,催化酶。这些修饰已成为人们非常感兴趣的主题,特别是,组蛋白修饰被认为在基因调控的多个方面发挥着关键作用,包括介导与染色质重塑因子的相互作用、一般或特定组织特异性转录的对接。最近,人们对组蛋白甲基化进行了深入研究,并且对特定甲基化标记组蛋白 H3 赖氨酸 79 的作用有了更深入的了解。 H3K79)由赖氨酸甲基转移酶 DOT1L 独特催化,多种证据表明其具有关键且特定的作用。 DOT1L 在心脏发生过程中和出生后心脏中在整个发育过程中在心脏中高度表达,并且 Dot1L 的整体消融导致妊娠中期致死,并且在妊娠中期用 αMHC-cre 消融心肌细胞会导致多种心血管异常。成人心脏心肌病的部分原因是抗肌营养不良蛋白基因表达的扰动,来自小鼠胚胎干细胞心肌细胞分化的证据表明,DOT1L 发挥着作用。在心肌细胞分化的早期阶段发挥着关键作用,但尚未有体内研究解决这个问题。因此,在初步研究中,我们利用 xMLCre 在 E7.5 处消除了 Dot1L,并发现突变体有心肌细胞增生,并在早期死亡。在围产期小鼠心肌细胞培养物中消除 Dot1L 的初步研究表明,Dot1L 调节心肌细胞周期的持续需要。总之,这些观察结果得出了我们的假设:胚胎、新生儿和成人阶段的心肌细胞需要 Dot1L 来调节心肌细胞周期和心肌细胞的渐进分化。根据假设,我们的具体目标是: 1) 表征早期心肌细胞特异性 Dot1L 突变体的心脏表型 2) 识别直接或间接调节的基因。 DOT1L 介导的体内 H3K79 甲基化 3) 检查出生后和成人心脏对 Dot1L 的需求,这些研究的结果将为了解 DOT1L 在不同发育阶段以及出生后和成人心脏中的作用提供机制。这些研究有望深入了解表观遗传修饰调节心肌细胞周期的机制,因此可能为发育中和成年心脏的心脏修复提供治疗方法。目前正在测试用于 MLL 相关白血病的治疗,因此我们的研究将为这些抑制剂的潜在心脏副作用提供信息。我们的研究还将探讨 DOT1L 抑制剂的未来潜力。
用于心脏再生疗法。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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SYLVIA M EVANS其他文献
SYLVIA M EVANS的其他文献
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{{ truncateString('SYLVIA M EVANS', 18)}}的其他基金
Renewing the heart: cardiomyocyte cell cycle regulation
更新心脏:心肌细胞细胞周期调节
- 批准号:
10112298 - 财政年份:2019
- 资助金额:
$ 38.75万 - 项目类别:
Renewing the heart: cardiomyocyte cell cycle regulation
更新心脏:心肌细胞细胞周期调节
- 批准号:
10350617 - 财政年份:2019
- 资助金额:
$ 38.75万 - 项目类别:
Renewing the heart: cardiomyocyte cell cycle regulation
更新心脏:心肌细胞细胞周期调节
- 批准号:
10581586 - 财政年份:2019
- 资助金额:
$ 38.75万 - 项目类别:
Renewing the heart: cardiomyocyte cell cycle regulation
更新心脏:心肌细胞细胞周期调节
- 批准号:
9893022 - 财政年份:2019
- 资助金额:
$ 38.75万 - 项目类别:
The Role of Dot1L in developing and postnatal heart
Dot1L 在发育和产后心脏中的作用
- 批准号:
8898912 - 财政年份:2014
- 资助金额:
$ 38.75万 - 项目类别:
REGULATORY GENOMIC STUDIES IN A COHORT OF IPS CELL DERIVED CARDIOMYOCYTES
IPS 细胞来源的心肌细胞群体的调控基因组研究
- 批准号:
8527970 - 财政年份:2011
- 资助金额:
$ 38.75万 - 项目类别:
REGULATORY GENOMIC STUDIES IN A COHORT OF IPS CELL DERIVED CARDIOMYOCYTES
IPS 细胞来源的心肌细胞群体的调控基因组研究
- 批准号:
8500437 - 财政年份:2011
- 资助金额:
$ 38.75万 - 项目类别:
REGULATORY GENOMIC STUDIES IN A COHORT OF IPS CELL DERIVED CARDIOMYOCYTES
IPS 细胞来源的心肌细胞群体的调控基因组研究
- 批准号:
8300829 - 财政年份:2011
- 资助金额:
$ 38.75万 - 项目类别:
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