The role for phase separation in oncogenesis and aberrant chromatin looping formation
相分离在肿瘤发生和异常染色质环形成中的作用
基本信息
- 批准号:10908136
- 负责人:
- 金额:$ 57.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-04 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAcute Myelocytic LeukemiaAutomobile DrivingBehavior ControlBindingBiological ModelsCellsChimera organismChromatinChromatin LoopChromatin Structure AlterationClinicalClustered Regularly Interspaced Short Palindromic RepeatsDNA BindingDNA Binding DomainDevelopmentDiseaseDissectionEnhancersExhibitsFingersFusion Oncogene ProteinsFutureGene ExpressionGene FusionGenesGenetic TranscriptionGenomeGenomicsGlycineGoalsHOXA9 geneHematologyHematopoietic NeoplasmsHematopoietic stem cellsHistonesHumanIn VitroLeukemic CellLiquid substanceMaintenanceMalignant NeoplasmsMediatingModelingMolecularMusN-terminalNuclear Pore Complex ProteinsOncogene ActivationOncogenesOncogenicOncoproteinsOutcomePatientsPhasePhenotypePhenylalaninePhysical condensationPlantsPrognosisProtein RegionProteinsProto-OncogenesPublic HealthRNA-Binding ProteinsRecurrenceResearchRoleTreatment Failureacquired factorcancer cellhomeodomaininsightleukemialeukemic transformationleukemogenesisnovelnovel therapeutic interventionprogramspromotertranscription factortumortumorigenesis
项目摘要
PROJECT SUMMARY/ABSTRACT
Rearrangement of NUP98 gene (NUP98-r) is recurrent in leukemias such as acute myeloid leukemia (AML).
Patients with NUP98-r show poor prognosis and therapy failure. Most NUP98-r partners (>30 identified from
patients) are a DNA-binding domain of transcription factor (TF; e.g. HOXA9) or a histone-binding motif such as
Plant Homeodomain (PHD), suggesting chromatin deregulation as an oncogenic mechanism. NUP98-r fusions
invariably retain Phenylalanine-Glycine (FG) repeats, termed intrinsically disordered region (IDR), from NUP98.
How unstructured IDR contributes to oncogenesis remains elusive. Our studies of NUP98-HOXA9, an AML
NUP98-TF chimera, unveil an essential requirement of NUP98’s IDR for liquid-liquid phase separation (LLPS).
We also show that IDR and LLPS are critical for the much-enhanced genome binding by NUP98-HOXA9 and
for long-distance chromatin looping between oncogene promoters and enhancers, leading to development of
aggressive AML in mice. Our unpublished preliminary studies of other recurrent leukemic fusions (namely,
NUP98-PHD fusions and MSI2-HOXA9, a leukemia-related chimera formed by fusing a less-studied IDR of an
RNA-binding protein with HOXA9’s DNA-binding domain) all point to involvements of IDR and LLPS for
oncogenesis. Thus, we hypothesize that, due to aberrant genic fusions, a number of leukemia-related onco-
TFs and chromatin factors acquire a phase-separation-inducing IDR to establish LLPS, which confers chimera
a much more enhanced ability in genomic targeting; consequently, an oncogenic gene-expression program is
over-activated while aberrant chromatin loops are formed between oncogene promoters and enhancers, which
drives formation of aggressive leukemias. Dissection of the mechanisms underlying the IDR- and phase-
separation-mediated aberrant genome organization and oncogene activation in cancer cells shall provide new
and paradigm-shifting views as for how aggressive cancer develops, implicative of potentially new treatments
in future. Towards this goal, we will further characterize the role for the un-studied IDR (that of MSI2) in
establishing LLPS in vitro and in cells (Aim 1A) and will use primary human hematopoietic stem/progenitor
cells (HSPCs) and derived cells to define roles of IDR and LLPS in regulating genomic targeting (1B), the
target gene expression (1C), and leukemic transformation in vitro/vivo (1D) by various fusions (NUP98-PHD
and MSI2/NUP98-HOXA9). LLPS-indued chromatin looping is CTCF-independent and represents a previously
unstudied mechanism underlying 3D chromatin organization. We will further define the 3D chromatin structure
alterations caused by various NUP98-r and MSI2-HOXA9 fusions in disease-relevant cells (Aim 2A), define the
molecular mechanisms driving formation/maintenance of LLPS-dependent loops (2B), and determine the
impact of LLPS DNA loops on the sustained activation of oncogenes by using a novel CRISPR/dCas9-IDR
fusion strategy (2C). As phase-separation-competent molecules are frequently implicated in a wide range of
human cancers and diseases, both the significance and overall impact of the project are potentially high.
项目总结/摘要
NUP 98基因重排(NUP 98-r)在白血病如急性髓性白血病(AML)中是复发性的。
NUP 98-r患者预后差,治疗失败。大多数NUP 98-r合作伙伴(从
患者)是转录因子(TF;例如HOXA 9)的DNA结合结构域或组蛋白结合基序,
植物同源结构域(PHD),提示染色质失调是一种致癌机制。NUP 98-r融合体
总是保留来自NUP 98称为固有无序区(IDR)的苯丙氨酸-甘氨酸(FG)重复序列。
非结构化的IDR如何促进肿瘤发生仍然是难以捉摸的。NUP 98-HOXA 9是一种急性髓细胞白血病,
NUP 98-TF嵌合体揭示了NUP 98 IDR对液-液相分离(LLPS)的基本要求。
我们还表明IDR和LLPS对于NUP 98-HOXA 9和H 0XA 9的增强的基因组结合是至关重要的。
癌基因启动子和增强子之间的长距离染色质环,导致
小鼠的侵袭性AML。我们对其他复发性白血病融合的未发表的初步研究(即,
NUP 98-PHD融合体和MSI 2-HOXA 9,一种白血病相关嵌合体,通过融合一种研究较少的白血病细胞的IDR而形成。
RNA结合蛋白与HOXA 9的DNA结合结构域)都指出IDR和LLPS参与
肿瘤发生因此,我们假设,由于异常的基因融合,一些白血病相关的肿瘤-
TF和染色质因子获得相分离诱导IDR以建立LLPS,其赋予嵌合体
基因组靶向能力大大增强;因此,
过度激活,同时在癌基因启动子和增强子之间形成异常染色质环,
导致恶性白血病的形成剖析IDR的机制-和阶段-
分离介导的异常基因组组织和癌基因激活在癌细胞中将提供新的
以及关于侵袭性癌症如何发展的范式转变观点,暗示着潜在的新治疗方法
日后为了实现这一目标,我们将进一步描述未研究的IDR(MSI 2)的作用,
在体外和细胞中建立LLPS(目标1A),并将使用原代人造血干/祖细胞
细胞(HSPC)和衍生细胞,以确定IDR和LLPS在调节基因组靶向中的作用(1B),
靶基因表达(1C)和通过各种融合(NUP 98-PHD)体外/体内白血病转化(1D
和MSI 2/NUP 98-HOXA 9)。LLPS诱导的染色质成环是CTCF独立的,代表了先前的
3D染色质组织的潜在机制尚未研究。我们将进一步定义3D染色质结构
在疾病相关细胞中由各种NUP 98-r和MSI 2-HOXA 9融合引起的改变(Aim 2A),定义了
驱动LLPS依赖性环形成/维持的分子机制(2B),并确定
通过使用新型CRISPR/dCas 9-IDR,LLPS DNA环对癌基因持续激活的影响
融合策略(2C)。由于具有相分离能力的分子经常涉及广泛的生物学领域,
人类癌症和疾病,该项目的重要性和总体影响可能很高。
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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Douglas H. Phanstiel其他文献
ALS-associated TDP-43 aggregates drive innate and adaptive immune cell activation
肌萎缩侧索硬化症(ALS)相关的TDP - 43聚集体驱动先天性和适应性免疫细胞活化
- DOI:
10.1016/j.isci.2025.112648 - 发表时间:
2025-06-20 - 期刊:
- 影响因子:4.100
- 作者:
Baggio A. Evangelista;Joey V. Ragusa;Kyle Pellegrino;Yijia Wu;Ivana Yoseli Quiroga-Barber;Shannon R. Cahalan;Omeed K. Arooji;Jillann A. Madren;Sally Schroeter;Joe Cozzarin;Ling Xie;Xian Chen;Kristen K. White;J. Ashley Ezzell;Marie A. Iannone;Sarah Cohen;Douglas H. Phanstiel;Rick B. Meeker;Todd J. Cohen - 通讯作者:
Todd J. Cohen
Proximity-dependent recruitment of Polycomb repressive complexes by the lncRNA emAirn/em
长链非编码 RNA emAirn 依赖于邻近性招募 Polycomb 抑制复合物
- DOI:
10.1016/j.celrep.2023.112803 - 发表时间:
2023-07-25 - 期刊:
- 影响因子:6.900
- 作者:
Aki K. Braceros;Megan D. Schertzer;Arina Omer;Jackson B. Trotman;Eric S. Davis;Jill M. Dowen;Douglas H. Phanstiel;Erez Lieberman Aiden;J. Mauro Calabrese - 通讯作者:
J. Mauro Calabrese
Douglas H. Phanstiel的其他文献
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{{ truncateString('Douglas H. Phanstiel', 18)}}的其他基金
The role for phase separation in oncogenesis and aberrant chromatin looping formation
相分离在肿瘤发生和异常染色质环形成中的作用
- 批准号:
10652637 - 财政年份:2022
- 资助金额:
$ 57.28万 - 项目类别:
The role for phase separation in oncogenesis and aberrant chromatin looping formation
相分离在肿瘤发生和异常染色质环形成中的作用
- 批准号:
10539807 - 财政年份:2022
- 资助金额:
$ 57.28万 - 项目类别:
MECHANISMS OF DYNAMIC CHROMATIN LOOPING DURING DIFFERENTIATION
分化过程中动态染色质环的机制
- 批准号:
10415986 - 财政年份:2018
- 资助金额:
$ 57.28万 - 项目类别:
MECHANISMS OF DYNAMIC CHROMATIN LOOPING DURING DIFFERENTIATION
分化过程中动态染色质环的机制
- 批准号:
10198946 - 财政年份:2018
- 资助金额:
$ 57.28万 - 项目类别:
Mechanisms of Dynamic Chromatin Looping During Differentiation - Common Fund Data Supplement
分化过程中动态染色质循环的机制 - 共同基金数据补充
- 批准号:
9983342 - 财政年份:2018
- 资助金额:
$ 57.28万 - 项目类别:
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