Epigenetic silencing of the osteoblast‐lineage gene program during hippocampal maturation. Issue 3 (2nd November 2020)

• Record Type: Journal Article
• Authors: Aguilar, Rodrigo; Bustos, Fernando J.; Nardocci, Gino; van Zundert, Brigitte; Montecino, Martin
• Is Part Of: Journal of cellular biochemistry. Volume 122:Issue 3/4(2021)
• Page Start: 367
• Page End: 384
• Publication Date: 2020-11-02
• Subjects: epigenetic control of gene transcription -- silencing of non‐neural genes in hippocampal cells; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.29865
• Languages: English
• ISSNs: 0730-2312

Abstract

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. Abstract : Neurons silence non‐neuronal genes through epigenetic mechanisms. The osteoblastic‐related genes Sp7 and Bglap are stably silenced in neural development and maturation through a mechanism involving H3K27me3 deposition and DNA methylation. Forced expression of the osteoblastic master regulator Runx2 in neurons de‐repress Sp7 gene expression and compromises neuronal development.