The Jurassic Park movies got the whole world excited about resurrecting dinosaurs from fossilized DNA, but more recent findings that the half-life of DNA is only 521 years mean that dream is science fiction. So, while the finer details of dinosaur genomes may be lost in the fossil record, new work has dug up epigenomic “fossils” of early development in our own genomes that can be brought back to life with (almost) as exciting implications. Histone modification and DNA methylation at enhancers are a key regulatory component of early development that are altered to inactivate specific enhancers as tissues differentiate. It’s not clear whether adult tissues maintain a recoverable memory of silenced enhancers. If they do, there are important implications for both learning how to better induce pluripotency and also better characterizing the development of various cancers.
The lab of Ramesh Shivdasani (Harvard, USA) set out to characterize the epigenetic changes at enhancers through development. They used mouse intestinal epithelial cells as a model, since they unlike most adult tissues, the cells descend lineally as they differentiate from a well-defined region of gut endoderm, without cellular admixture. They FACS sorted epithelial cells from both embryonic and adult intestinal epithelium from various stages of differentiation and performed various ChIP-seq (active enhancer marks H3K4me1, H3K27ac, and inactivating H3K27me3), RNA-seq, and whole genome bisulfite sequencing (WGBS) experiments.
Here’s what they uncovered:
adult cells, there are ~32,000 regions far from transcription start sites with
low (<50%) CpG methylation without active enhancer marks (H3K4me1 & H3K27ac),
greatly outnumbering active enhancers
- These represent a nearly complete (~90%) record of enhancers active during embryonic development and were identified by comparing to embryonic tissue
of PRC2 in intestine using a Cre/lox system in adulthood enables activation of embryonic enhancers
via accumulation of H3K27ac and loss of H3K27me3
- This occurred at nearly all embryonic enhancers, and exclusively at these loci
- Embryonic enhancers were reactivated (i.e. positively influencing local gene expression) in reverse chorological order to their inactivation during development
Senior author Ramesh Shivdasani remarks, “Beyond the sheer existence of this archive, we were surprised to find that it doesn’t remain permanently locked away but can be accessed by cells under certain conditions. The implications of this discovery for how we think about cells’ capabilities, and for the future treatment of degenerative and other diseases, are potentially profound.”
These findings open up new promise for research into regenerative medicine and possible novel cancer treatments. So, while embryonic enhancers may not be as flashy as a genetically modified T-rex, they may a part of ushering other futuristic advancements.
Dig up all the details of this fossil record over at Cell, March 2019