Epigenetic silencing of the osteoblast-lineage gene program during hippocampal maturation

Rodrigo Aguilar, Fernando J. Bustos, Gino Nardocci, Brigitte van Zundert, Martin Montecino

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Accumulating evidence indicates that epigenetic control of gene expression plays a significant role during cell lineage commitment and subsequent cell fate maintenance. Here, we assess epigenetic mechanisms operating in the rat brain that mediate silencing of genes that are expressed during early and late stages of osteogenesis. We report that repression of the osteoblast master regulator Sp7 in embryonic (E18) hippocampus is mainly mediated through the Polycomb complex PRC2 and its enzymatic product H3K27me3. During early postnatal (P10), juvenile (P30), and adult (P90) hippocampal stages, the repressive H3K27me3 mark is progressively replaced by nucleosome enrichment and increased CpG DNA methylation at the Sp7 gene promoter. In contrast, silencing of the late bone phenotypic Bglap gene in the hippocampus is PRC2-independent and accompanied by strong CpG methylation from E18 through postnatal and adult stages. Forced ectopic expression of the primary master regulator of osteogenesis Runx2 in embryonic hippocampal neurons activates the expression of its downstream target Sp7 gene. Moreover, transcriptomic analyses show that several genes associated with the mesenchymal-osteogenic lineages are transcriptionally activated in these hippocampal cells that express Runx2 and Sp7. This effect is accompanied by a loss in neuronal properties, including a significant reduction in secondary processes at the dendritic arbor and reduced expression of critical postsynaptic genes like PSD95. Together, our results reveal a developmental progression in epigenetic control mechanisms that repress the expression of the osteogenic program in hippocampal neurons at embryonic, postnatal, and adult stages.

Original languageEnglish
Pages (from-to)367-384
Number of pages18
JournalJournal of Cellular Biochemistry
Volume122
Issue number3-4
DOIs
StatePublished - Apr 2021
Externally publishedYes

Bibliographical note

Funding Information:
This study has been supported by FONDECYT 1170878 and FONDAP 15090007 (to MM), FONDECYT 1181645 (to BvZ), ANID PIA/BASAL AFB 170005 CARE UC (to BvZ), Nucleus UNAB DI‐4‐17/N (to BvZ), and ANID‐PAI 77180077 (to FB and MM).

Funding Information:
This study has been supported by FONDECYT 1170878 and FONDAP 15090007 (to MM), FONDECYT 1181645 (to BvZ), ANID PIA/BASAL AFB 170005 CARE UC (to BvZ), Nucleus UNAB DI-4-17/N (to BvZ), and ANID-PAI 77180077 (to FB and MM).

Publisher Copyright:
© 2020 Wiley Periodicals LLC

Keywords

  • epigenetic control of gene transcription
  • silencing of non-neural genes in hippocampal cells

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