No abstract

Highlights d Ablated intestinal stem cells (ISC) restore largely by crypt cell dedifferentiation d ISC-restricted transcription factor ASCL2 is required for this adaptive regeneration d Both absorptive and secretory lineages contribute to ISC restoration d ASCL2-dependent IL11RA1 activity enhances ISC recovery from dedifferentiating cells

No abstract

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 ciselements 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 ciselement 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. SUMMARYDeveloping 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.

Highlights d EZH2 loss reduces all H3K27me3 equally; 40% retained marks keep target genes silent d Replicational dilution is the major path for mammalian cells to clear H3K27me3 d H3K27me3 levels halve at each cell division irrespective of nucleosomal location d The balance of promoter H3K4me2/3 and H3K27me3 levels determines gene activity