Recruitment of CTCF to an Fto enhancer is responsible for transgenerational inheritance of BPA-induced obesity.
Yoon Hee JungHsiao-Lin V WangDaniel RuizBrianna J BixlerHannah LinsenbaumJian-Feng XiangSamantha ForestierAndrew M ShafikPeng JinVictor G CorcesPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- weight loss
- high fat diet induced
- metabolic syndrome
- insulin resistance
- type diabetes
- genome wide
- bariatric surgery
- transcription factor
- high glucose
- diabetic rats
- weight gain
- gene expression
- adipose tissue
- dna methylation
- binding protein
- drug induced
- spinal cord
- pregnant women
- mitochondrial dna
- dna binding
- dna damage
- copy number
- oxidative stress
- genome wide identification
- skeletal muscle
- endothelial cells
- genome wide analysis