Racial Disparities and Colorectal DNA Methylation- Driven Gene Expression

种族差异和结直肠 DNA 甲基化驱动的基因表达

基本信息

批准号：
10726172
负责人：
Li Li
金额：
$ 41.53万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10726172
关键词：
Aberrant DNA Methylation Acceleration African American population Age Aging American Anatomy Biological Biology Biopsy Chronology Clinical Colon Colon Carcinoma Colonic Neoplasms Colorectal Colorectal Cancer Colorectal Neoplasms DNA Methylation Data Deceleration Development Diagnosis Disease Environmental Exposure Epidemiology Epigenetic Process Ethnic Origin Etiology European Exhibits Gene Expression Gene Expression Profile Genes Genetic Transcription Genome Heterogeneity Human Hypermethylation Incidence Individual Left Lesion Link Location Methylation Molecular Multiple Anatomic Sites Normal tissue morphology Obesity Organoids Pathway interactions Patients Positioning Attribute Prevention strategy Race Rectum Residual state Risk Risk Assessment Risk Factors Sampling Side Site Smoking Tissues Triplet Multiple Birth age related carcinogenesis cohort colon carcinogenesis colon tumorigenesis colorectal cancer risk comparative follow-up genome-wide insight methylome mortality novel racial difference racial disparity racial diversity rectal response transcriptome transcriptome sequencing transcriptomics tumor

项目摘要

ABSTRACT Racial disparities in colorectal cancer (CRC) are widening. There are well-documented racial differences in anatomical location distribution of CRC. African Americans (AAs) are more likely to develop right side CRC and diagnosed at younger age than European Americans (EAs). The mechanisms underlying these observed racial disparities and the relationship to sidedness remain poorly understood. DNA methylation is a key epigenetic regulator of transcription. Epigenetic alterations result in accelerated aging and changes in gene expression, which are believed to drive colon tumorigenesis. In a recent study of colorectal biopsies from 128 patients, we discovered that human colon exhibits remarkable racial and side differences in DNA methylation and epigenetic aging. The right colon of AAs shows enrichment of hypermethylated differentially-methylated positions (DMPs) and accelerated epigenetic aging whereas the right colon of EAs shows decelerated aging as compared to left colon. Our analysis of rectal DNA methylation shows similar racial differences. We further show that in patient-derived normal colon organoids, response to environmental exposures is colon side specific and impacts global gene expression, further implying differing biology between right vs left colon, and vs rectum. These novel observations led to our central hypothesis that there are distinct epigenetic and transcriptomic perturbations underlying racial disparities in the development of site-specific colorectal neoplasia. We here propose to perform RNA-sequencing of 384 individual-matched triplet colorectal biopsies (right vs. left colon vs. rectum) from the 128 patients in our hands. In combination with DNA methylation data already generated on these patients, we will use a supervised approach to integrate omics data on the transcriptome and methylome, and to identify DNA methylation-driven gene expression signatures that may provide biological insight of the racial disparities and colorectal site differences observed. In Aim 1, we will identify within-individual site-specific DNA methylation-associated gene expression signatures across colorectum locations (right vs left colon vs rectum). In Aim 2, we will identify cross-individual racial differences in site-specific DNA methylation-associated gene expression signatures. In Aim 3, we will identify gene expression signatures associated with site- and race-specific epigenetic age acceleration. Our study will provide novel insight of the epigenetic and transcriptomic underpinnings of racial disparities in risk of site specific CRC, and guide the development of prevention strategies to reduce racial disparities by targeting critical epigenetic/transcriptomic pathways linked to colon carcinogenesis.

抽象的结直肠癌（CRC）的种族差异正在扩大。有详细记录的种族 CRC 解剖位置分布的差异。非裔美国人 (AA) 更有可能发展正确的权利结直肠癌的诊断年龄比欧洲美国人 (EA) 更年轻。这些背后的机制观察到的种族差异及其与偏向性的关系仍然知之甚少。 DNA甲基化是一种转录的关键表观遗传调节因子。表观遗传改变导致加速衰老和基因变化表达，据信这会驱动结肠肿瘤的发生。最近对 128 名患者进行结直肠活检的研究我们发现人类结肠在 DNA 甲基化方面表现出显着的种族和侧面差异和表观遗传衰老。 AA 的右结肠显示高甲基化差异甲基化的富集位置（DMP）和加速的表观遗传衰老，而 EA 的右结肠显示减缓衰老与左结肠相比。我们对直肠 DNA 甲基化的分析显示出类似的种族差异。我们进一步表明在患者来源的正常结肠类器官中，对环境暴露的反应是结肠侧具体并影响全局基因表达，进一步暗示右结肠和左结肠之间的生物学差异，以及与直肠。这些新颖的观察结果得出了我们的中心假设，即存在独特的表观遗传和特定位点结直肠发育中种族差异背后的转录组扰动瘤形成。我们在此建议对 384 个个体匹配的三联体结直肠活检进行 RNA 测序（右结肠与左结肠与直肠）来自我们手中的 128 名患者。结合DNA甲基化数据已经在这些患者上生成，我们将使用监督方法来整合有关这些患者的组学数据转录组和甲基化组，并识别 DNA 甲基化驱动的基因表达特征，这些特征可能提供对观察到的种族差异和结直肠部位差异的生物学见解。在目标 1 中，我们将识别个体内特定位点 DNA 甲基化相关基因表达特征结直肠位置（右结肠、左结肠、直肠）。在目标 2 中，我们将识别跨个体的种族差异位点特异性 DNA 甲基化相关基因表达特征。在目标 3 中，我们将识别基因与位点和种族特异性表观遗传年龄加速相关的表达特征。我们的研究将提供对位点风险种族差异的表观遗传学和转录组学基础的新见解具体的《儿童权利公约》，并指导制定预防战略，以减少种族差异与结肠癌发生相关的关键表观遗传/转录组途径。