Abstract
Ezh2 is a catalytic subunit of the polycomb repressive complex 2 (PRC2) which mediates epigenetic gene silencing through depositing the mark histone H3 lysine 27 trimethylation (H3K27me3) at target genomic sequences. Previous studies have demonstrated that Enhancer of Zeste Homolog 2 (Ezh2) was differentially expressed during maturation of hippocampal neurons; in immature neurons, Ezh2 was abundantly expressed, whereas in mature neurons the expression Ezh2 was significantly reduced. Here, we report that Ezh2 is downregulated by microRNAs (miRs) that are expressed during the hippocampal maturation process. We show that, in mature hippocampal neurons, lethal-7 (let-7) and microRNA-124 (miR-124) are robustly expressed and can target cognate motifs at the 3′-UTR of the Ezh2 gene sequence to downregulate Ezh2 expression. Together, these data demonstrate that the PRC2 repressive activity during hippocampal maturation is controlled through a post-transcriptional mechanism that mediates Ezh2 downregulation in mature neurons.
Highlights
Several reports have demonstrated the critical role of epigenetic mechanisms during control of gene expression associated with the physiological function of the central nervous system (CNS) in mammals [1,2]
Our results indicated that an important component mediating this Enhancer of Zeste Homolog 2 (Ezh2) downregulation during hippocampal maturation could involve transcriptional inhibition of the Ezh2 gene, additional evidence has demonstrated the contribution of post-transcriptional and post-translational mechanisms, including the role of microRNAs [10] and ubiquitin-dependent proteasome degradation [11]
We report that miR-124 and let-7, which are among the group of miRs that are highly expressed in mature hippocampal neurons, can target cognate motifs at the Ezh2 3 -UTR, and thereby dampen Ezh2 expression
Summary
Several reports have demonstrated the critical role of epigenetic mechanisms during control of gene expression associated with the physiological function of the central nervous system (CNS) in mammals [1,2]. Mammals contain a let-7 family, including several members (from let-7a to let-7k), which have been shown to play a significant role in maintaining the balance between neuronal progenitor cell proliferation and commitment to engage neurogenic differentiation, as they control the expression of a number of genes that are critical during this early developmental stages [35,36,37,38]. Loss of let-7 function in these tumor cells resulted in increased Ezh expression that was accompanied by acquisition of a cancer stem cell signature Whereas these data provide support for a regulatory role of miRs over PRC2 expression and function during early neuron lineage commitment, there is a lack of studies that address the contribution of miRs during the maturation of hippocampal neurons, a process that determines the functionality of these cells during learning and memory. ProbeSetID rno-miR-103_st rno-miR-99a_st rno-miR-107_st rno-miR-16_st rno-miR-138_st rno-miR-24_st rno-miR-22_st rno-let-7a_st rno-miR-181a_st rno-miR-191_st rno-miR-23a_st rno-let-7d_st rno-miR-26a_st rno-let-7e_st rno-miR-125a-5p_st rno-miR-130a_st rno-miR-127_st rno-miR-99b_st
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