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Mol Cell. 2019 Mar 15. pii: S1097-2765(19)30135-2. doi: 10.1016/j.molcel.2019.02.024. [Epub ahead of print]

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

Author information

1
Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4
Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
5
Molecular Biology Core Facility, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
6
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
7
Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham & Women's Hospital, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: ramesh_shivdasani@dfci.harvard.edu.

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 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.

KEYWORDS:

DNA hypomethylation; decommissioned developmental genes; epigenetic memory

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