Role of lncRNA mediated R-loops in CTCF boundary function and AML genome organization
lncRNA介导的R环在CTCF边界功能和AML基因组组织中的作用
基本信息
- 批准号:10384074
- 负责人:
- 金额:$ 64.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-12-03 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaBindingBinding SitesBiologicalCell LineChIP-seqChromatinClustered Regularly Interspaced Short Palindromic RepeatsDNADataData SetDiseaseEnhancersEpigenetic ProcessGene Expression ProfileGene MutationGenesGenetic TranscriptionGenomeGenomicsGoalsHematopoietic stem cellsHi-CHomeobox GenesHybridsLeadMLL-rearranged leukemiaMediatingMolecularMutationOutputPathogenesisRNARNA immunoprecipitation sequencingRegulationRoleSamplingSiteStructureTestingTranscriptional RegulationTransgenic OrganismsUntranslated RNAWorkacute myeloid leukemia cellbeta catenincell behaviorchromatin isolation by RNA purification sequencingcohesincohesiongenomic locushematopoietic stem cell self-renewalimprovedleukemialeukemic transformationleukemogenesismouse modelnoveloverexpressionprogramspromotersuccesstranscriptome sequencing
项目摘要
Abstract:
Acute myeloid leukemia (AML) is a heterogeneous disorder of hematopoietic stem and progenitor cells
(HSPCs) associated with sequential acquisition of driver gene mutations. These mutations often lead to altered
genome organization and transcriptional programs that perturb HSC self-renewal and differentiation. Recently,
we discovered that HOTTIP, a posterior HOXA-associated long non-coding RNA (lncRNA), remodels CTCF-
defined topologically associated domains (TADs). This remodeling regulates the homeotic gene-associated
leukemic transcription program and facilitates AML leukemogenesis, driven by MLL rearrangement (MLLr+) or
NMP1 mutation (NPM1C+). One of the top HOTTIP-regulated transcription motifs in AML is CTCF-binding sites
(CBSs), suggesting a novel function of HOTTIP in regulating CTCF-mediated genome organization and AML
pathogenesis. Indeed, combined RNA-seq, ChIRP-seq, and CTCF ChIP-seq analyses revealed that HOTTIP
co-occupied with CTCF in a subset of the AML genome, including HOXA and WNT/β-catenin target gene loci,
for their activation. However, it remains unknown whether and how HOTTIP lncRNA directly regulates CTCF-
directed genome organization to promote leukemic transcription networks and leukemogenesis. Our preliminary
data showed that HOTTIP is capable of directly interacting with key TAD boundary CBSs in the HOXA and WNT
target loci via formation of an R-loop structure. We hypothesize that HOTTIP activation mediates aberrant R-
loop formation in CBSs to stratify CTCF chromatin boundary for reprograming AML TADs and leukemic
transcription networks, leading to HSPC perturbation and leukemogenesis. To test this hypothesis, we will focus
on the impact of the altered CTCF TAD boundary and R-loop formation upon HOTTIP activation on AML genome
regulation and gene transcription output. In this proposal we will test the importance of the HOTTIP activation-
mediated aberrant R-loop formation in modulating the CTCF boundary activity and transcriptional regulation in
AML. Specifically, we will identify and characterize critical HOTTIP-regulated CTCF chromatin boundaries in the
AML genome. We will then define the novel role of R-loops in HOTTIP-mediated CTCF chromatin boundary
definition and genome organization. Finally, we will assess the impact of the HOTTIP-mediated aberrant R-loop
formation at specific TAD boundaries on leukemogenesis and HSPC regulation.
摘要:
急性髓系白血病是一种造血干细胞和祖细胞的异质性疾病
(HSPC)与驱动基因突变的顺序获得相关。这些突变通常会导致
干扰HSC自我更新和分化的基因组组织和转录程序。最近,
我们发现HOTTIP,一种后部HOXA相关的长非编码RNA(lncRNA),重塑CTCF,
拓扑关联域(Topologically Associated Domains,TADs)这种重塑调节同源异型基因相关的
白血病转录程序和促进AML白血病发生,由MLL重排(MLLR+)驱动,或
NMP 1突变(NPM 1C+)。在AML中,HOTTIP调控的最重要的转录基序之一是CTCF结合位点
(CBS),表明HOTTIP在调节CTCF介导的基因组组织和AML中的新功能
发病机制事实上,结合RNA-seq、ChIRP-seq和CTCF ChIP-seq分析显示,HOTTIP
在AML基因组的一个亚组中与CTCF共占据,包括HOXA和WNT/β-连环蛋白靶基因座,
为了他们的激活。然而,HOTTIP lncRNA是否以及如何直接调节CTCF仍然是未知的。
定向基因组组织以促进白血病转录网络和白血病发生。我们的初步
数据表明,HOTTIP能够直接与HOXA和WNT中的关键边界CBS相互作用
通过形成R环结构靶向基因座。我们假设HOTTIP激活介导了异常的R-
CBS中形成环以分层CTCF染色质边界,用于重编程AML TAD和白血病
转录网络,导致HSPC扰动和白血病发生。为了验证这一假设,我们将重点
关于改变的CTCF边界和R环形成对AML基因组上HOTTIP活化的影响
调节和基因转录输出。在本提案中,我们将测试HOTTIP激活的重要性-
介导的异常R环形成在调节CTCF边界活性和转录调节中的作用。
急性髓细胞白血病具体来说,我们将确定和表征关键的HOTTIP调节的CTCF染色质边界,
AML基因组。然后,我们将定义R环在HOTTIP介导的CTCF染色质边界中的新作用。
定义和基因组组织。最后,我们将评估HOTTIP介导的异常R环的影响,
在白血病发生和HSPC调节的特定边界上形成。
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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{{ truncateString('Suming Huang', 18)}}的其他基金
Role of lncRNA mediated R-loops in CTCF boundary function and AML genome organization
lncRNA介导的R环在CTCF边界功能和AML基因组组织中的作用
- 批准号:
10534236 - 财政年份:2021
- 资助金额:
$ 64.2万 - 项目类别:
Role of lincRNAs in HSC function and leukemogenesis
lincRNA 在 HSC 功能和白血病发生中的作用
- 批准号:
10312758 - 财政年份:2019
- 资助金额:
$ 64.2万 - 项目类别:
Role of lincRNAs in HSC function and leukemogenesis
lincRNA 在 HSC 功能和白血病发生中的作用
- 批准号:
10064721 - 财政年份:2019
- 资助金额:
$ 64.2万 - 项目类别:
Regulation of TAL1/SCL in T-Cell Leukemia
T 细胞白血病中 TAL1/SCL 的调控
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10094201 - 财政年份:2017
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The Role of Long Noncoding RNA in Hematopoiesis
长链非编码 RNA 在造血中的作用
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9523246 - 财政年份:2016
- 资助金额:
$ 64.2万 - 项目类别:
The role of a lincRNA in chromatin structure and hematopoiesis
lincRNA 在染色质结构和造血中的作用
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7837522 - 财政年份:2009
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Regulation of insulator function and globin gene expression by USF and associated
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8034359 - 财政年份:2009
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Regulation of insulator function and globin gene expression by USF and associated
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8213390 - 财政年份:2009
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Regulation of insulator function and globin gene expression by USF and associated
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