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。有记录在案的种族 结直肠癌解剖位置分布的差异。非裔美国人(AA)更有可能发展成正确的 与欧洲裔美国人(EAs)相比，该病的诊断年龄较小。这些问题背后的机制 观察到的种族差异及其与偏袒的关系仍然鲜为人知。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，这被认为是推动结肠肿瘤发生的原因。在最近对128例大肠活检的研究中 我们发现人类结肠在DNA甲基化方面表现出显著的种族和侧方差异。 和表观遗传衰老。AAS的右半结肠表现为高度甲基化和差异甲基化 体位(DMP)和加速的表观遗传老化，而EAS的右半结肠表现为减速衰老 与左半结肠相比。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 结果表明，在患者来源的正常结肠有机物质中，对环境暴露的反应是结肠一侧。 并影响全球基因表达，进一步暗示了右结肠和左结肠之间的不同生物学特征，以及 VS直肠。这些新的观察结果导致了我们的中心假设，即存在明显的表观遗传和 部位特异性结直肠发育中潜在的种族差异的转录干扰 肿瘤。我们建议对384例个体匹配的三联体大肠活检标本进行RNA测序。 (右半结肠与左半结肠对比直肠)来自我们手上的128名患者。结合DNA甲基化数据 已经在这些患者身上生成的数据，我们将使用一种监督方法来整合 转录组和甲基组，并识别可能由DNA甲基化驱动的基因表达特征 提供对观察到的种族差异和结直肠部位差异的生物学洞察。在目标1中，我们将 确定个体内特定部位的DNA甲基化相关基因表达特征 结肠直肠位置(右半结肠与左半结肠对比直肠)。在目标2中，我们将确定跨个人的种族差异 在特定部位的DNA甲基化相关基因表达特征中。在目标3中，我们将识别基因 与特定部位和特定种族表观遗传年龄加速相关的表达特征。我们的研究将 为表观遗传学和转录学基础上的种族差异提供了新的见解 具体的《儿童权利公约》，并指导制定预防战略，通过有针对性地减少种族差距 关键的表观遗传/转录途径与结肠癌的发生有关。

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.