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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.

摘要