Racial Disparities and Colorectal DNA Methylation- Driven Gene Expression

摘要 结直肠癌（CRC）的种族差异正在扩大。有充分的证据表明， 结直肠癌的解剖位置分布差异。非裔美国人（AAs）更有可能发展为 CRC和诊断在年轻的年龄比欧洲美国人（EAs）。这些潜在的机制 人们对观察到的种族差异及其与偏袒的关系仍然知之甚少。DNA甲基化是 转录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改变 表达，这被认为是驱动结肠肿瘤发生。在最近对128例结直肠活检的研究中 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AAs的右半结肠显示高甲基化的差异甲基化的 位置（DMPs）和加速的表观遗传衰老，而EA的右半结肠显示出减速衰老， 与左结肠相比。我们对直肠DNA甲基化的分析显示了类似的种族差异。我们进一步 显示在患者来源正常结肠类器官中，对环境暴露的响应是结肠侧的 特异性和影响全局基因表达，进一步表明右结肠与左结肠之间的生物学差异， 与直肠相比。这些新的观察导致了我们的中心假设，即存在不同的表观遗传和 转录组学紊乱是发生部位特异性结直肠癌的种族差异的基础 肿瘤形成我们在此建议对384例个体匹配的三联体结直肠活检标本进行RNA测序 （右结肠与左结肠与直肠）。结合DNA甲基化数据 已经在这些患者身上产生的，我们将使用一种监督的方法来整合组学数据， 转录组和甲基化组，并确定DNA甲基化驱动的基因表达签名， 提供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 鉴定个体内位点特异性DNA甲基化相关基因表达特征 结肠直肠位置（右结肠vs左结肠vs直肠）。在目标2中，我们将识别跨个体种族差异 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 提供了新的见解的表观遗传和转录组学基础的种族差异的风险，网站 具体的《儿童权利公约》，并指导制定预防战略， 与结肠癌发生相关的关键表观遗传/转录组学途径。

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.