The impact of changes in chromatin architecture on cancer phenotypes and tumor progression
The impact of changes in chromatin architecture on cancer phenotypes and tumor progression
批准号:
10153720
负责人:
Jane Amanda Skok
金额:
$210.72万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-06-12 至 2024-05-31
关键词:
3-DimensionalAffectAnimalsArchitectureAutomobile DrivingBindingBiological AssayCREBBP geneCancer BiologyCellsChromatinChromosome StructuresChromosomesClinicalComplexDNADNA BindingDNA MethylationDataDevelopmentDrug TargetingEP300 geneEnhancersEnzymesEpigenetic ProcessGene ExpressionGenesGenetic TranscriptionGenomeGenomicsHematologic NeoplasmsHistonesHumanLaboratoriesLengthLinkMalignant - descriptorMalignant NeoplasmsMediatingMediator of activation proteinModelingMorphologic artifactsMutateMutationNOTCH1 geneOncogenicPathologyPathway interactionsPatientsPatternPhenotypePlayPolycombProteinsQuality ControlResolutionRoleScienceSomatic MutationSpecimenStandardizationStructureTechnologyTestingTranscriptional RegulationValidationbasecell typecohesincomputerized data processingepigenomegenetic regulatory proteinhuman diseaseinsightnew therapeutic targetprogramspromoterprotein complexrecruitthree dimensional structuretranscription factortumortumor progressiontumorigenesistumorigenic
中文摘要
摘要--总体
新出现的数据表明,基因集合被组织成边界划定的区域和子区域,
其中存在表观遗传标记和转录状态的高度协调。越大
域被定义为分别由活动和非活动组成的隔室A和B
染色质。这些结构域可以分解为保守的TADS(拓扑相关结构域)。后者是
由高度自相互作用的区域组成,由绝缘边界隔开。以更高的分辨率
在水平上,基因表达是通过将细胞上下文特定的基因增强子循环到内部的启动子来实现的,
而且很少会超出TAD的界限。最保守的TAD结构接触是由
至少部分是通过CTCF、DNA结合因子和边界因子以及
虽然细胞类型的特异性增强子-启动子相互作用是由粘附素促进的,但
介体复合体和细胞转录因子。值得注意的是,CTCF和粘附素复合体经常在
并在正常的发育和分化途径中发挥关键作用。他们也可以直接
与肿瘤相关的转录因子和组蛋白修饰复合体相互作用或间接控制
转型。基于这些概念,我们的P01提出了以下总体假设:体细胞突变
CTCF或粘附素调节剂破坏染色质的结构组织(影响TAD和亚TAD
边界和增强子相互作用),并通过这一机制建立致癌的表观遗传学和
转录程序。相反,我们认为建筑蛋白复合体的招募也是
被特定转录因子、组蛋白修饰酶和组蛋白修饰酶的体细胞突变或放松调控所干扰
控制DNA甲基化的酶,将这些变化置于染色体变化的上游
建筑作为肿瘤发生的原因。为了测试我们的模型,我们的目标是比较基因突变对
CTCF、粘附素卸载因子Pds5B和控制增强子功能的蛋白质(NOTCH1
癌基因转录因子、组蛋白修饰酶如Polycomb和CREBBP/EP300以及
改变DNA甲基化状态的酶)。我们将重点关注恶性血液病:(一)
确定CTCF和粘附素调节蛋白Pds5B的突变是否以及如何破坏正常
发展和诱导恶性转化;(Ii)确定3D染色体的变化
CTCF或粘附素调节因子突变引起的体系结构,Pds5B诱导致癌表观遗传学和
转录编程;(Iii)确定转录因子和表观遗传修饰物的突变
通过对3D染色体结构的影响来推动恶性转化;以及(Iv)确定
靶向转录因子活性和表观遗传修饰物的药物可以纠正
致癌染色体结构。
英文摘要
SUMMARY - OVERALL
Emerging data indicate that sets of genes are organized into boundary delimited territories and sub-territories,
within which there is a high level of coordination of epigenetic marks and transcriptional states. The larger
domains have been defined as compartments A and B that are respectively comprised of active and inactive
chromatin. These can be broken down into conserved TADs (topologically associated domains). The latter are
composed of highly self-interacting regions, segregated by insulated boundaries. At an even higher resolution
level, gene expression is conferred through looping of cell context specific gene enhancers to promoters within,
and less frequently beyond TAD boundaries. The most conserved TAD structural contacts are mediated and
regulated at least in part through the action of CTCF, a DNA binding TF and boundary factor, along with the
cohesin complex, while cell-type specific enhancer-promoter interactions are facilitated by cohesin, the
mediator complex and cell transcription factors. Notably, CTCF and the cohesin complex are often mutated in
cancer and play critical roles in normal development and differentiation pathways. They may also directly
interact with, or indirectly control transcription factors and histone modifying complexes linked to malignant
transformation. Based on these notions, our P01 proposes the following overall hypothesis: Somatic mutations
of CTCF or cohesin regulators disrupt the architectural organization of chromatin (affecting TAD, and sub-TAD
boundaries and enhancer interactions) and through this mechanism establish oncogenic epigenetic and
transcriptional programs. Conversely, we propose that recruitment of architectural protein complexes are also
disrupted by somatic mutation or deregulation of specific transcription factors, histone modifying enzymes and
enzymes controlling DNA methylation, which place these changes upstream of alterations in chromosome
architecture as a cause of tumorigenesis. To test our model we aim to compare the impact of mutations in
CTCF, the cohesin unloading factor PDS5B, and proteins that control enhancer function (the NOTCH1
oncogenic transcription factor, histone modifying enzymes such as Polycomb and CREBBP/EP300, as well as
enzymes that alter DNA methylation status DNMT3A). Focusing on hematologic malignancies we will: (i)
determine whether and how mutations of Ctcf and the cohesin regulatory protein, Pds5b disrupt normal
development and induce malignant transformation; (ii) determine how alterations in 3D chromosomal
architecture caused by mutation of Ctcf or the cohesin regulator, Pds5b induce tumorigenic epigenetic and
transcriptional programming; (iii) Determine whether transcription factors and mutations of epigenetic modifiers
drive malignant transformation through effects on 3D chromosomal architecture; and (iv) determine whether
drugs targeting transcription factor activity and epigenetic modifiers can `correct; the deleterious effects of
oncogenic chromosomal architecture.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
The impact of changes in chromatin architecture on cancer phenotypes and tumor progression
-
批准号:10402270
-
项目类别:
-
资助金额:$198.49万
-
财政年份:2019
-
负责人:Jane Amanda Skok
-
依托单位:
Project 1: The biochemical, topological and functional impact of cancer associated Ctcfmutations and their contribution to cancer
-
批准号:10652280
-
项目类别:
-
资助金额:$40.34万
-
财政年份:2019
-
负责人:Jane Amanda Skok
-
依托单位:
Project 1: The biochemical, topological and functional impact of cancer associated Ctcfmutations and their contribution to cancer
-
批准号:10153721
-
项目类别:
-
资助金额:$41.47万
-
财政年份:2019
-
负责人:Jane Amanda Skok
-
依托单位:
The impact of changes in chromatin architecture on cancer phenotypes and tumor progression
-
批准号:10652279
-
项目类别:
-
资助金额:$198.49万
-
财政年份:2019
-
负责人:Jane Amanda Skok
-
依托单位:
Administrative Core
-
批准号:10402274
-
项目类别:
-
资助金额:$16.02万
-
财政年份:2019
-
负责人:Jane Amanda Skok
-
依托单位:
Project 1: The biochemical, topological and functional impact of cancer associated Ctcfmutations and their contribution to cancer
-
批准号:10402271
-
项目类别:
-
资助金额:$31.94万
-
财政年份:2019
-
负责人:Jane Amanda Skok
-
依托单位:
Administrative Core
-
批准号:10153724
-
项目类别:
-
资助金额:$16.62万
-
财政年份:2019
-
负责人:Jane Amanda Skok
-
依托单位:
Administrative Core
-
批准号:10652285
-
项目类别:
-
资助金额:$13.89万
-
财政年份:2019
-
负责人:Jane Amanda Skok
-
依托单位:
Nuclear organization and its role in gene regulation
-
批准号:10406421
-
项目类别:
-
资助金额:$74.24万
-
财政年份:2017
-
负责人:Jane Amanda Skok
-
依托单位:
Nuclear organization and its role in gene regulation
-
批准号:10591590
-
项目类别:
-
资助金额:$74.24万
-
财政年份:2017
-
负责人:Jane Amanda Skok
-
依托单位:
Mechanisms Underlying the Control of Recombination and Gene Regulation
-
批准号:9897581
-
项目类别:
-
资助金额:$71.35万
-
财政年份:2017
-
负责人:Jane Amanda Skok
-
依托单位:
Mechanisms Underlying the Control of Recombination and Gene Regulation
-
批准号:9276345
-
项目类别:
-
资助金额:$49.6万
-
财政年份:2017
-
负责人:Jane Amanda Skok
-
依托单位:
Enhancer Driven Gene Regulation During Lymphocyte Development
-
批准号:8748701
-
项目类别:
-
资助金额:$52.52万
-
财政年份:2014
-
负责人:Jane Amanda Skok
-
依托单位:
The Role of RNA in Regulating recombination and allelic exclusion
-
批准号:8670698
-
项目类别:
-
资助金额:$25.43万
-
财政年份:2013
-
负责人:Jane Amanda Skok
-
依托单位:
The Role of RNA in Regulating recombination and allelic exclusion
-
批准号:8565997
-
项目类别:
-
资助金额:$19.92万
-
财政年份:2013
-
负责人:Jane Amanda Skok
-
依托单位:
Spatiotemporal control of recombination by the RAG proteins and ATM
-
批准号:7943941
-
项目类别:
-
资助金额:$50.0万
-
财政年份:2009
-
负责人:Jane Amanda Skok
-
依托单位:
Spatiotemporal control of recombination by the RAG proteins and ATM
-
批准号:7820887
-
项目类别:
-
资助金额:$50.0万
-
财政年份:2009
-
负责人:Jane Amanda Skok
-
依托单位:
Co-ordination of recombination and allelic exclusion at IgH and Igk loci
-
批准号:7813032
-
项目类别:
-
资助金额:$42.25万
-
财政年份:2009
-
负责人:Jane Amanda Skok
-
依托单位:
Co-ordination of recombination and allelic exclusion at IgH and Igk loci
-
批准号:7884272
-
项目类别:
-
资助金额:$33.56万
-
财政年份:2008
-
负责人:Jane Amanda Skok
-
依托单位:
Co-ordination of recombination and allelic exclusion at IgH and Igk loci
-
批准号:8105495
-
项目类别:
-
资助金额:$33.23万
-
财政年份:2008
-
负责人:Jane Amanda Skok
-
依托单位:
海外基金