β-Arrestin1/miR-326 Transcription Unit Is Epigenetically Regulated in Neural Stem Cells Where It Controls Stemness and Growth Arrest.

Agnese Po,Marco Tafani,Vincenzo Alfano,Elisabetta Ferretti,Alessandra Vacca,Giuseppina Catanzaro,Evelina Miele,Felice Giangaspero,Maddalena Napolitano,Luana Abballe,Franco Locatelli,Zein Mersini Besharat,Federica Begalli

doi:10.1155/2017/5274171

Agnese Po, Marco Tafani + Show 11 more

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https://doi.org/10.1155/2017/5274171

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Abstract

Cell development is regulated by a complex network of mRNA-encoded proteins and microRNAs, all funnelling onto the modulation of self-renewal or differentiation genes. How intragenic microRNAs and their host genes are transcriptionally coregulated and their functional relationships for the control of neural stem cells (NSCs) are poorly understood. We propose here the intragenic miR-326 and its host gene β-arrestin1 as novel players whose epigenetic silencing maintains stemness in normal cerebellar stem cells. Such a regulation is mediated by CpG islands methylation of the common promoter. Epigenetic derepression of β-arrestin1/miR-326 by differentiation signals or demethylating agents leads to suppression of stemness features and cell growth and promotes cell differentiation. β-Arrestin1 inhibits cell proliferation by enhancing the nuclear expression of the cyclin-dependent kinase inhibitor p27. Therefore, we propose a new mechanism for the control of cerebellar NSCs where a coordinated epigenetic mechanism finely regulates β-arrestin1/miR-326 expression and consequently NSCs stemness and cell growth.

Highlights

Neural stem cells (NSCs) are believed to foster a hierarchical developmental program in which self-renewal and pluri/multipotency are responsible for the expansion and/or the maintenance of an uncommitted cell population pool
Transcription of both intergenic and intragenic miRNAs may be regulated by their own promoters, whether some intragenic miRNAs share promoters with their host genes that generate pre-miRNA and mRNA, both arising from the same transcript [5, 6]
We found that, when shifted to differentiation medium, NSCs increased βarr-1 level was paralleled by an activation of p27 transcription and the increase of p27 protein in the nucleus as observed in nucleous/cytoplasmic fractionation experiment (Figure 5)

Summary

Introduction

Neural stem cells (NSCs) are believed to foster a hierarchical developmental program in which self-renewal and pluri/multipotency are responsible for the expansion and/or the maintenance of an uncommitted cell population pool. Recent evidences have highlighted the crucial role of microRNAs (miRNAs) in conferring neural cell identities during neural induction, neuronal differentiation, and subtype specification [3]. MiRNAs are widespread throughout the genome, where they can be found in either intergenic or intragenic (especially intronic) regions [4]. Transcription of both intergenic and intragenic miRNAs may be regulated by their own promoters, whether some intragenic miRNAs share promoters with their host genes that generate pre-miRNA and mRNA, both arising from the same transcript [5, 6]. The consequent spatial and temporal coexpression implies a functional relationship between the intragenic miRNA and its host gene

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