A Statistical Approach to Identifying Significant Transgenerational Methylation Changes

TL;DR

This paper introduces GISAIM, a statistical method to identify significant transgenerational methylation changes, and demonstrates its application in studying how maternal diet influences cancer risk across multiple generations.

Contribution

The paper presents GISAIM, a novel statistical approach for detecting inherited methylation alterations, and applies it to reveal epigenetic inheritance of cancer risk due to maternal dietary exposures.

Findings

Maternal high fat and estrogenic diets increase mammary cancer risk in offspring.

Transgenerational methylation changes are associated with altered gene expression.

Cancer risk inheritance involves DNA methylation changes across generations.

Abstract

Epigenetic aberrations have profound effects on phenotypic output. Genome wide methylation alterations are inheritable to pass down the aberrations through multiple generations. We developed a statistical method, Genome-wide Identification of Significant Methylation Alteration, GISAIM, to study the significant transgenerational methylation changes. GISAIM finds the significant methylation aberrations that are inherited through multiple generations. In a concrete biological study, we investigated whether exposing pregnant rats (F0) to a high fat (HF) diet throughout pregnancy or ethinyl estradiol (EE2)-supplemented diet during gestation days 14 20 affects carcinogen-induced mammary cancer risk in daughters (F1), granddaughters (F2) and great-granddaughters (F3). Mammary tumorigenesis was higher in daughters and granddaughters of HF rat dams, and in daughters, granddaughters and great-granddaughters of EE2 rat dams. Outcross experiments showed that increased mammary cancer risk was transmitted to HF granddaughters equally through the female or male germlines, but is only transmitted to EE2 granddaughters through the female germline. Transgenerational effect on mammary cancer risk was associated with increased expression of DNA methyltransferases, and across all three EE2 generations hypo or hyper methylation of the same 375 gene promoter regions in their mammary glands. Our study shows that maternal dietary estrogenic exposures during pregnancy can increase breast cancer risk in multiple generations of offspring, and the increase in risk may be inherited through non-genetic means, possibly involving DNA methylation.