Mechanisms of enhancer regulation in leukemia
白血病增强子调控机制
基本信息
- 批准号:10321638
- 负责人:
- 金额:$ 49.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAdultAnimal ModelArchitectureB-LymphocytesBindingBiologicalBiologyBloodCell LineCell LineageCell modelCellsCervicalChromosomesChronic Lymphocytic LeukemiaClustered Regularly Interspaced Short Palindromic RepeatsColon CarcinomaComplexDNA Polymerase IIDNA-Directed RNA PolymeraseDataDevelopmentDiseaseEndometrialEnhancersEnsureEpigenetic ProcessFBXW7 geneGene ExpressionGenerationsGenesGeneticGenetic TranscriptionGenomicsGrowthHeadHematopoieticHematopoietic NeoplasmsHematopoietic stem cellsHumanIn VitroLaboratoriesLeadLesionLightLungMacromolecular ComplexesMalignant - descriptorMalignant NeoplasmsMapsMature B-LymphocyteMediatingMediator of activation proteinMolecularMusMutagenesisMutateMutationPatientsPharmacologyPhosphotransferasesProteinsPublishingRecurrenceRegulationRoleSamplingScientistSolidSolid NeoplasmSomatic MutationSpecialistStudy modelsTailTechniquesTestingTransgenic MiceTranslatingTumor Suppressor ProteinsWestern Worldadult leukemiabasecell transformationchromosome conformation capturechronic lymphocytic leukemia cellflexibilitygain of functiongenomic locushematopoietic stem cell differentiationin vivoinsightlarge cell Diffuse non-Hodgkin&aposs lymphomaleukemiamembermicrodeletionmouse modelmultidisciplinarymutantnew therapeutic targetnovelpre-clinicalprogramspromoterprotein expressionrecruitsmall moleculestem cell functionstem cell survivaltooltranscription factortranscriptometumortumorigenesisubiquitin ligaseunpublished works
项目摘要
ABSTRACT
Transcription factors require coactivators to communicate with the general transcription machinery and,
thereby, ensure that biological inputs are translated into specific gene-expression programs. The Mediator
complex is such a coactivator and acts as a ‘molecular bridge’ between transcription factor at enhancers and
RNA polymerase II (Pol II) at promoters. It is a large macromolecular complex further arranged in four modules
that confer high flexibility: the head, the middle, the tail and the kinase module. The member of the kinase
module Mediator 12 (MED12) has been found frequently mutated in both solid (endometrial, lung, cervical,
colon carcinomas) and blood (DLBCL, CLL, ALL, AML) cancers. However, the underlying mechanisms of
MED12 mutations and its role in disease initiation and progression remain elusive. We have recently focused
on the function of the kinase module and specifically MED12 in hematopoietic stem cell (HSC) differentiation
and transformation. We found that MED12 protein expression is controlled post-translationally by the ubiquitin
ligase FBXW7, a frequently mutated tumor suppressor. We also found that MED12 is an essential regulator of
HSC function, as in vivo deletion of MED12 compromises HSC survival and leads to mouse lethality. Together
with essential hematopoietic transcription factors, MED12 co-occupies HSC-specific enhancers. MED12
depletion destabilizes P300 binding thus leading to rapid enhancer “inactivation”, and loss of expression of key
HSC-specific genes. These data suggest that MED12 expression and function can be altered due to multiple
mechanisms, including somatic mutations targeting the gene itself or its regulators (FBXW7), and that this
aberrant function can lead to malignant transformation. This proposal aims to shed light on the molecular
mechanisms altered upon deregulation of a crucial regulator of enhancer activity, such as MED12. While it has
been suggested that MED12 mutations confer a “gain-of-function”, no mechanistic studies have been
performed up to date. To address this key question, we are studying chronic lymphocytic leukemia (CLL), the
most common adult leukemia in the western world. To dissect how disruption of Mediator function contributes
to this heterogeneous and complex disease, we use a combination of: a) transcriptional/epigenetic
characterization of human patient samples harboring MED12 mutations, b) CRISPR-modified and ES targeted
transgenic mouse models to investigate the ability of MED12 lesions to initiate and maintain disease, and, c) in
vitro transcriptome, epigenetic and 3D-chromosome topology in CRISPR-modified cell lines with MED12
mutations. Defining the mechanisms by which Mediator and enhancer regulation contribute to malignant
transformation will be beneficial for the development of novel therapies targeting blood malignancies and solid
tumors. The recent identification of small molecules targeting Mediator pharmacologically suggests that such
therapies are within reach.
摘要
转录因子需要辅激活子来与一般的转录机制通信,
从而确保生物输入被翻译成特定的基因表达程序。调解员
复合物是这样的共激活剂,并作为增强子处的转录因子和
RNA聚合酶II(Pol II)在启动子处。它是一个大分子复合物,进一步排列在四个模块中
赋予高度灵活性的结构:头部、中部、尾部和激酶模块。激酶的成员
已发现模块介体12(MED 12)在实体(子宫内膜,肺,宫颈,
结肠癌)和血癌(DLBCL、CLL、ALL、AML)。然而,
MED 12突变及其在疾病发生和进展中的作用仍然难以捉摸。我们最近专注于
激酶模块,特别是MED 12在造血干细胞(HSC)分化中的功能
和转变。我们发现MED 12蛋白的表达是在表达后由泛素化的
连接酶FBXW 7,一种经常突变的肿瘤抑制因子。我们还发现,MED 12是一种重要的调节因子,
HSC功能,因为MED 12的体内缺失损害HSC存活并导致小鼠致死。一起
与必需的造血转录因子一起,MED 12共占据HSC特异性增强子。MED12
耗尽使P300结合不稳定,从而导致快速增强子“失活”,并使关键蛋白表达丧失。
HSC特异性基因这些数据表明,MED 12的表达和功能可以由于多种因素而改变。
机制,包括靶向基因本身或其调节因子(FBXW 7)的体细胞突变,并且这
功能异常可导致恶性转化。该提案旨在阐明分子
在增强子活性的关键调节因子如MED 12的失调后改变的机制。虽然它有
虽然MED 12突变被认为具有“功能获得性”,但尚未进行机制研究。
执行到最新。为了解决这个关键问题,我们正在研究慢性淋巴细胞白血病(CLL),
是西方世界最常见的成人白血病剖析中介功能的破坏如何有助于
对于这种异质性和复杂的疾病,我们使用以下组合:a)转录/表观遗传
表征携带MED 12突变的人类患者样品,B)CRISPR修饰的和ES靶向的
转基因小鼠模型,以研究MED 12损伤引发和维持疾病的能力,和,c)在
MED 12修饰的CRISPR细胞系中的体外转录组、表观遗传和3D染色体拓扑
突变。定义介导和增强子调控有助于恶性肿瘤的机制
转化将有利于开发针对血液恶性肿瘤和实体瘤的新疗法。
肿瘤的最近鉴定出的靶向介导蛋白的小分子表明,
治疗是触手可及的。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Iannis Aifantis其他文献
Iannis Aifantis的其他文献
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{{ truncateString('Iannis Aifantis', 18)}}的其他基金
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炎症在急性髓系白血病免疫反应调节中的作用
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Dissecting innate immune signaling in pre-leukemia evolution
剖析白血病前期进化中的先天免疫信号
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10584536 - 财政年份:2022
- 资助金额:
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Dissecting innate immune signaling in pre-leukemia evolution
剖析白血病前期进化中的先天免疫信号
- 批准号:
10462192 - 财政年份:2022
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mRNA stability and its impact on hematopoiesis and acute leukemia
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- 批准号:
10339742 - 财政年份:2022
- 资助金额:
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mRNA stability and its impact on hematopoiesis and acute leukemia
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10543125 - 财政年份:2022
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Regulation of emergency hematopoiesis by the ubiquitin-proteasome system
泛素-蛋白酶体系统对紧急造血的调节
- 批准号:
10279596 - 财政年份:2021
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$ 49.24万 - 项目类别:
Regulation of emergency hematopoiesis by the ubiquitin-proteasome system
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