Transgenerational self-reconstruction of disrupted chromatin organization after exposure to an environmental stressor in mice

Exposure to environmental stressors is known to increase disease susceptibility in unexposed descendants in the absence of detectable genetic mutations. The mechanisms mediating environmentally-induced transgenerational disease susceptibility are poorly understood. We showed that great-great-grandsons of female mice exposed to tributyltin (TBT) throughout pregnancy and lactation were predisposed to obesity due to altered chromatin organization that subsequently biased DNA methylation and gene expression. Here we analyzed DNA methylomes and transcriptomes from tissues of animals ancestrally exposed to TBT spanning generations, sexes, ontogeny, and cell differentiation state. We found that TBT elicited concerted alterations in the expression of “chromatin organization” genes and inferred that TBT-disrupted chromatin organization might be able to self-reconstruct transgenerationally. We also found that the location of “chromatin organization” and “metabolic” genes is biased similarly in mouse and human genomes, suggesting that exposure to environmental stressors in different species could elicit similar phenotypic effects via self-reconstruction of disrupted chromatin organization. Overall design: We generated RNA-Seq data from mesenchymal stem cells (MSCs) from 8-week old F3 and F4, female and male mice and liver from 33-week old F4 male mice ancestrally exposed to DMSO (0.1%) or TBT (50 nM ) during in utero development and lactation. N=5 per treatment for MSCs and N=4 per treatment for liver--> 48 RNA-seq samples in total We generated MBD-Seq data from mesenchymal stem cells (MSCs) from 8-week old F3 and F4, female and male mice and liver from 33-week old F4 male mice ancestrally exposed to DMSO (0.1%) or TBT (50 nM ) during in utero development and lactation. N=5 per treatment for MSCs and N=4 per treatment for liver--> 48 MBD-seq samples in total