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Author Notes:

Victor G. Corces, vgcorces@gmail.com

Y.H.J., H.-L.V.W., P.J., and V.G.C. designed research; Y.H.J., H.-L.V.W., D.R., B.J.B., H.L., J.-F.X., S.F., and A.M.S. performed research; Y.H.J., H.-L.V.W., D.R., B.J.B., and V.G.C. analyzed data; and Y.H.J., H.-L.V.W., D.R., and V.G.C. wrote the paper.

We would like to thank Dr. Cynthia Vied at the Translational Science Laboratory of Florida State University for help with Illumina sequencing; Drs. Karolina Piotrowska-Nitsche and Christopher Raymond from the Emory Mouse Transgenic and Gene Targeting Core for their assistance with the IVF experiments and the generation of Ftocstrains. This work was supported by US Public Health Service Awards R01 ES027859 and P30ES019776 (V.G.C.); R35 NS111602, R01 HG008935, U01 MH116441 (P.J.) from the NIH. H.-L.V.W. was supported by NIH F32 ES031827, D.R. was supported by NIH F32 ES034241, and B.J.B. was supported by NIH T32 GM008490. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

The authors declare no competing interest.

Subject:

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • chromatin
  • transcription
  • sperm
  • oocyte
  • fertilization
  • BISPHENOL-A
  • EXPOSURE
  • CHROMATIN
  • RNA
  • CONTRIBUTE
  • BINDING
  • VARIANT

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

Tools:

Journal Title:

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Volume:

Volume 119, Number 50

Publisher:

, Pages e2214988119-e2214988119

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2022 the Author(s). Published by PNAS.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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