A Molecular Case Series: Deep Cellular and Spatial Epigenetic Characterization of Human Colorectal Cancer

分子案例系列：人类结直肠癌的深层细胞和空间表观遗传特征

基本信息

批准号：
10677611
负责人：
Nathan J. Spix
金额：
$ 4.67万
依托单位：
VAN ANDEL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677611
关键词：
Aberrant DNA Methylation Address Awareness Bioinformatics Case Series Cell division Cells Cellularity Clinical Clonal Expansion Collaborations Colon Carcinoma Colorectal Colorectal Cancer Colorectal Neoplasms Complex DNA Methylation DNA Modification Methylases DNA Sequence Alteration DNA mapping Data Data Set Deposition Development Disease Doctor of Philosophy Early treatment Environment Epigenetic Process Etiology Event Evolution Exhibits Frequencies Gene Frequency Gene Targeting Genes Genetic Genetic Transcription Goals Growth Heterogeneity Histologic Human Hypermethylation Immune Individual Intestinal Polyps Joints Knowledge Laboratories Large Intestine Carcinoma Learning Libraries Link Malignant - descriptor Malignant Neoplasms Measures Mediating Medicine Mentorship Methylation Michigan Modeling Molecular Mucous Membrane Mutation Normal tissue morphology Pattern Play Polycomb Recurrence Research Training Resolution Resources Role Sampling Scientist Spatial Distribution System Techniques Testing The Cancer Genome Atlas Time Tissue Sample Tissues Training Training Programs Transcriptional Regulation Tumor Expansion Universities WNT Signaling Pathway Work age related base bisulfite sequencing cancer genome cancer initiation college colorectal cancer progression colorectal cancer treatment design driver mutation experimental study genetic variant genome-wide genomic locus histological specimens insight mouse model neoplastic cell permissiveness programs promoter prospective screening segregation single cell analysis stem cells tumor tumor progression whole genome

Aberrant DNA Methylation Address Awareness Bioinformatics Case Series Cell division Cells Cellularity Clinical Clonal Expansion Collaborations Colon Carcinoma Colorectal Colorectal Cancer Colorectal Neoplasms Complex DNA Methylation DNA Modification Methylases DNA Sequence Alteration DNA mapping Data Data Set Deposition Development Disease Doctor of Philosophy Early treatment Environment Epigenetic Process Etiology Event Evolution Exhibits Frequencies Gene Frequency Gene Targeting Genes Genetic Genetic Transcription Goals Growth Heterogeneity Histologic Human Hypermethylation Immune Individual Intestinal Polyps Joints Knowledge Laboratories Large Intestine Carcinoma Learning Libraries Link Malignant - descriptor Malignant Neoplasms Measures Mediating Medicine Mentorship Methylation Michigan Modeling Molecular Mucous Membrane Mutation Normal tissue morphology Pattern Play Polycomb Recurrence Research Training Resolution Resources Role Sampling Scientist Spatial Distribution System Techniques Testing The Cancer Genome Atlas Time Tissue Sample Tissues Training Training Programs Transcriptional Regulation Tumor Expansion Universities WNT Signaling Pathway Work age related base bisulfite sequencing cancer genome cancer initiation college colorectal cancer progression colorectal cancer treatment design driver mutation experimental study genetic variant genome-wide genomic locus histological specimens insight mouse model neoplastic cell permissiveness programs promoter prospective screening segregation single cell analysis stem cells tumor tumor progression whole genome

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项目摘要

PROJECT SUMMARY/ABSTRACT Cancer has long been thought of as a disease caused by genetic mutations that enable a cell to grow out of control. However, there is growing awareness of the importance of epigenetic aberrations – disruptions in the systems that control the transcriptional potential of genes – in cancer initiation and progression. Sufficient levels of DNA methyltransferase activity, which are responsible for the deposition of DNA methylation (an important epigenetic mark), have been shown to be necessary for formation of intestinal polyps in mouse models of colorectal cancer (CRC). Furthermore, hypermethylation of many genetic loci has been noted in CRC tissue samples. These hypermethylated loci are significantly enriched in genes targeted by the polycomb repressive complex (Polycomb Target Genes or PTGs), which play important roles in development and differentiation. Thus, suppression of PTGs by aberrant DNA methylation could contribute to the development and progression of CRC. However, it is unclear when and where these PTG hypermethylation (PTGH) events arise. They may arise as a result of genetic mutations, but studies of the cancer genome have failed to find any mutation linked to PTGH. Also, PTGH events have been found in histologically normal colorectal tissue. Thus, it is possible that PTGH accumulates over time in normal colorectal tissue, with excessive levels of this mark allowing malignant transformation. If this is the case, at least some PTGH events should be found clonally (in every cell of a tumor), because they existed in the founding cell of the tumor. The experiments outlined here are designed to test this model by constructing a detailed map of DNA methylation in human colorectal tumors and adjacent mucosa. Specifically, they aim to test the hypotheses that 1) PTGH exists in tumor-adjacent colorectal mucosa in a spatial and cellular distribution consistent with accumulation over time, and that 2) PTGH events are clonally present within CRC tumors. To achieve these goals, the proposed studies use bulk and single-cell whole-genome bisulfite sequencing techniques to measure genome-wide DNA methylation at single-base resolution. These studies will greatly strengthen our understanding of the cellular and spatial distribution of PTGH in CRC, giving us a better understanding of when and where this mark arises. Ultimately, these findings could help to develop more sensitive screening tests or earlier treatments for colorectal cancer. These studies will be conducted as part of the applicant’s training in a joint MD-PhD program sponsored by Michigan State University College of Human Medicine and Van Andel Institute (VAI). VAI provides a rich environment for research training, combining ample scientific resources with opportunities to learn from world- class scientists in a focused setting. The applicant will receive mentorship from leading experts in the field of DNA methylation, single-cell analysis, and bioinformatics, as well as many opportunities for collaboration, professional development, and continued clinical activity throughout the training program.

项目摘要/摘要长期以来，人们一直认为癌症是由基因突变引起的疾病，使细胞能够生长失控。但是，人们对表观遗传畸变的重要性的认识越来越控制基因转录潜力的系统 - 在癌症的倡议和进展中。充足的 DNA甲基转移酶活性的水平，这些水平负责DNA甲基化的沉积重要的表观遗传标记），已证明是在小鼠模型中形成肠道息肉必不可少的结直肠癌（CRC）。此外，在CRC组织中已经注意到了许多遗传局部的高甲基化样品。这些高甲基化的局部体显着富集了由多孔反射性靶向的基因复合物（polycomb靶基因或PTG），在开发和分化中起重要作用。那，异常DNA甲基化对PTG的抑制可能有助于CRC的发展和发展。但是，目前尚不清楚这些PTG高甲基化（PTGH）发生在何时何地发生。他们可能由于基因突变而引起的，但是对癌症基因组的研究未能找到任何相关的突变到ptgh。同样，在组织学正常的结直肠组织中发现了PTGH事件。那可能有可能 PTGH随着时间的时间在正常的结直肠组织中积累转型。如果是这种情况，则至少应该在克隆（在肿瘤的每个细胞中）发现一些PTGH事件，因为它们存在于肿瘤的基础中。此处概述的实验旨在测试通过在人结直肠肿瘤和邻近粘膜中构造DNA甲基化的详细图表来模型。具体而言，它们旨在测试1）PTGH存在于肿瘤粘膜中的PTGH的假设。和细胞分布与随着时间的积累一致，并且2）PTGH事件是克隆的在CRC肿瘤内。为了实现这些目标，拟议的研究使用批量和单细胞全基因组亚硫酸盐测序技术以单基分辨率测量全基因组DNA甲基化。这些研究将极大地增强我们对CRC中PTGH的细胞和空间分布的理解，从而使我们对何时何地出现的何时何地更好地理解。最终，这些发现可能有助于发展对结直肠癌的更敏感的筛查测试或更早的治疗方法。这些研究将作为申请人在MD-PHD计划中的培训的一部分进行。密歇根州立大学人类医学院和范·安德尔研究所（VAI）。 Vai提供了富人研究培训的环境，将充足的科学资源与向世界学习的机会相结合 - 集体式的班级科学家。申请人将获得该领域的主要专家 DNA甲基化，单细胞分析和生物信息学以及许多合作的机会，在整个培训计划中，专业发展以及持续的临床活动。