The impact of changes in chromatin architecture on cancer phenotypes and tumor progression

染色质结构的变化对癌症表型和肿瘤进展的影响

基本信息

批准号：
10652279
负责人：
Jane Amanda Skok
金额：
$ 198.49万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2019-06-12 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10652279
关键词：
3-Dimensional Affect Animals Architecture Automobile Driving Binding Biological Assay CREBBP gene Cancer Biology Cells Chromatin Chromosome Structures Chromosomes Clinical Complex DNA DNA Binding DNA Methylation DNMT3a Data Development Drug Targeting EP300 gene Enhancers Enzymes Epigenetic Process Gene Expression Gene Structure Genes Genetic Transcription Genome Genomics Hematologic Neoplasms Histones Human Laboratories Length Link Malignant - descriptor Malignant Neoplasms Mediating Mediator Modeling Morphologic artifacts Mutate Mutation NOTCH1 gene Oncogenic Pathology Pathway interactions Patients Pattern Phenotype Physically Challenged Play Polycomb Proteins Quality Control Resolution Role Science Somatic Mutation Specimen Standardization Technology Testing Transcriptional Regulation Validation cell type cohesin computerized data processing epigenome genetic regulatory protein human disease insight new therapeutic target programs promoter protein complex recruit segregation three dimensional structure transcription factor tumor tumor progression tumorigenesis tumorigenic

项目摘要

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.

摘要 - 总体新出现的数据表明，基因组被组织成边界划分的区域和子区域，其中表观遗传标记和转录状态具有高度协调性。较大的域被定义为区室 A 和 B，分别由活性和非活性组成染色质。这些可以分解为保守的 TAD（拓扑相关域）。后者是由高度自相互作用的区域组成，由绝缘边界隔离。以更高的分辨率在水平上，基因表达是通过细胞环境特异性基因增强子与启动子的循环而赋予的，并且很少会超出 TAD 边界。最保守的 TAD 结构接触是介导的至少部分通过 CTCF、DNA 结合 TF 和边界因子以及粘连蛋白复合物，而细胞类型特异性增强子-启动子相互作用是由粘连蛋白促进的，介导复合物和细胞转录因子。值得注意的是，CTCF 和粘连蛋白复合物经常在癌症并在正常发育和分化途径中发挥关键作用。他们也可以直接与恶性相关的转录因子和组蛋白修饰复合物相互作用或间接控制转变。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 或粘连蛋白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）并通过这种机制建立致癌表观遗传和转录程序。相反，我们建议结构蛋白复合物的招募也因体细胞突变或特定转录因子、组蛋白修饰酶的失调而破坏控制 DNA 甲基化的酶，将这些变化置于染色体改变的上游结构作为肿瘤发生的原因。为了测试我们的模型，我们的目标是比较突变的影响 CTCF、粘连蛋白卸载因子 PDS5B 和控制增强子功能的蛋白质（NOTCH1 致癌转录因子、组蛋白修饰酶（例如 Polycomb 和 CREBBP/EP300）以及改变 DNA 甲基化状态的酶 DNMT3A)。重点关注血液系统恶性肿瘤，我们将：(i) 确定 Ctcf 和粘连蛋白调节蛋白 Pds5b 的突变是否以及如何破坏正常发育并诱发恶变； (ii) 确定 3D 染色体如何改变由 Ctcf 或粘连蛋白调节因子突变引起的结构，Pds5b 诱导致瘤性表观遗传和转录编程； (iii) 确定转录因子和表观遗传修饰剂的突变是否通过影响 3D 染色体结构来驱动恶性转化； (iv) 确定是否针对转录因子活性和表观遗传修饰剂的药物可以“纠正”；的有害影响致癌染色体结构。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Somatic Focal Copy Number Gains of Noncoding Regions of Receptor Tyrosine Kinase Genes in Treatment-Resistant Epilepsy.

难治性癫痫中受体酪氨酸激酶基因非编码区的体细胞局灶拷贝数增加。

DOI：
发表时间：
2021
期刊：
影响因子：
3.2
作者：
Vasudevaraja, Varshini;Rodriguez, Javier Hernaez;Pelorosso, Cristiana;Zhu, Kaicen;Buccoliero, Anna Maria;Onozato, Maristela;Mohamed, Hussein;Serrano, Jonathan;Tredwin, Lily;Garonzi, Marianna;Forcato, Claudio;Zeck, Briana;Ramaswami, Sitharam;S
通讯作者：
S

The novel lncRNA BlackMamba controls the neoplastic phenotype of ALK- anaplastic large cell lymphoma by regulating the DNA helicase HELLS.

新型 lncRNA BlackMamba 通过调节 DNA 解旋酶 HELLS 来控制 ALK 间变性大细胞淋巴瘤的肿瘤表型。

DOI：
发表时间：
2020
期刊：
影响因子：
11.4
作者：
Fragliasso, Valentina;Verma, Akanksha;Manzotti, Gloria;Tameni, Annalisa;Bareja, Rohan;Heavican, Tayla B;Iqbal, Javeed;Wang, Rui;Fiore, Danilo;Mularoni, Valentina;Chan, Wing C;Lhoumaud, Priscillia;Skok, Jane;Zanetti, Eleonora;Merli, Francesco
通讯作者：
Merli, Francesco

In Vivo and Ex Vivo Patient-Derived Tumor Xenograft Models of Lymphoma for Drug Discovery.

用于药物发现的体内和离体患者来源的淋巴瘤异种移植模型。

DOI：
发表时间：
2021-04
期刊：
影响因子：
0
作者：
Cacciapuoti, Maria Teresa;Cappelli, Luca Vincenzo;Fiore, Danilo;Toruno, Pedro;Kayembe, Clarisse;Tam, Wayne;Inghirami, Giorgio
通讯作者：
Inghirami, Giorgio