Extensive Recovery of Embryonic Enhancer and Gene Memory Stored in Hypomethylated Enhancer DNA

• Published in: Molecular cell 2019-05, Vol.74 (3), p.542-554.e5
• Main Authors: Jadhav, Unmesh, Cavazza, Alessia, Banerjee, Kushal K., Xie, Huafeng, O’Neill, Nicholas K., Saenz-Vash, Veronica, Herbert, Zachary, Madha, Shariq, Orkin, Stuart H., Zhai, Huili, Shivdasani, Ramesh A.
• Format: Article
• Language: English
• Subjects: Animals; decommissioned developmental genes; DNA hypomethylation; DNA Methylation - genetics; Enhancer Elements, Genetic - genetics; epigenetic memory; Epigenomics; Gene Expression Regulation, Developmental - genetics; Histones - genetics; Mice
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.02.024

Developing and adult tissues use different cis-regulatory elements. Although DNA at some decommissioned embryonic enhancers is hypomethylated in adult cells, it is unknown whether this putative epigenetic memory is complete and recoverable. We find that, in adult mouse cells, hypomethylated CpG dinucleotides preserve a nearly complete archive of tissue-specific developmental enhancers. Sites that carry the active histone mark H3K4me1, and are therefore considered “primed,” are mainly cis elements that act late in organogenesis. In contrast, sites decommissioned early in development retain hypomethylated DNA as a singular property. In adult intestinal and blood cells, sustained absence of polycomb repressive complex 2 indirectly reactivates most—and only—hypomethylated developmental enhancers. Embryonic and fetal transcriptional programs re-emerge as a result, in reverse chronology to cis element inactivation during development. Thus, hypomethylated DNA in adult cells preserves a “fossil record” of tissue-specific developmental enhancers, stably marking decommissioned sites and enabling recovery of this epigenetic memory. [Display omitted] •Hypomethylated DNA preserves nearly complete catalogs of developmental enhancers•Adult H3K4me1+H3K27ac− enhancers are not poised but remnants of fetal gene activity•TFs relieved of PRC2 repression selectively reactivate hypomethylated enhancers•Recommissioned enhancers drive tissue-specific fetal and embryonic gene activity Although cells decommission embryonic enhancers by erasing histone marks, these regions retain hypomethylated DNA into adulthood, preserving an accurate archive of tissue-specific developmental cis elements. This epigenetic memory is recovered after prolonged absence of polycomb repressive complex 2, when transcription factors selectively reactivate hypomethylated developmental enhancers and their tissue-restricted target genes.