Recruitment of CTCF to an Fto enhancer is responsible for transgenerational inheritance of BPA-induced obesity

• Type of Material: Article
• Authors: Yoon Hee Jung, Emory University; Hsiao-Lin V. Wang, Emory University; Daniel Ruiz, Emory University; Brianna J Bixler, Emory University; Hannah Linsenbaum, Emory University; Jian-Feng Xiang, Emory University; Samantha Forestier, Emory University; Andrew Shafik, Emory University; Peng Jin, Emory University; Victor Corces, Emory University
• Language: English
• Date: 2022-12-13
• Publisher: NATL ACAD SCIENCES
• Publication Version: Final Published Version
• Copyright Statement: © 2022 the Author(s). Published by PNAS.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.2214988119
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 119
• Issue: 50
• Start Page: e2214988119
• End Page: e2214988119
• Keywords: oocyte; RNA; chromatin; Science & Technology; CONTRIBUTE; Multidisciplinary Sciences; BINDING; fertilization; sperm; EXPOSURE; transcription; CHROMATIN; Science & Technology - Other Topics; VARIANT; BISPHENOL-A
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

The mechanisms by which environmentally-induced epiphenotypes are transmitted transgenerationally in mammals are poorly understood. Here we show that exposure of pregnant mouse females to bisphenol A (BPA) results in obesity in the F2 progeny due to increased food intake. This epiphenotype can be transmitted up to the F6 generation. Analysis of chromatin accessibility in sperm of the F1–F6 generations reveals alterations at sites containing binding motifs for CCCTC-binding factor (CTCF) at two cis-regulatory elements (CREs) of the Fto gene that correlate with transmission of obesity. These CREs show increased interactions in sperm of obese mice with the Irx3 and Irx5 genes, which are involved in the differentiation of appetite-controlling neurons. Deletion of the CTCF site in Fto results in mice that have normal food intake and fail to become obese when ancestrally exposed to BPA. The results suggest that epigenetic alterations of Fto can lead to the same phenotypes as genetic variants.