Uncovering the roles of long noncoding RNAs in neural development and glioma progression - PubMed (original) (raw)

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Uncovering the roles of long noncoding RNAs in neural development and glioma progression

Alexander D Ramos et al. Neurosci Lett. 2016.

Abstract

In the past decade, thousands of long noncoding RNAs (lncRNAs) have been identified, and emerging data indicate that lncRNAs can have important biological functions and roles in human diseases including cancer. Many lncRNAs appear to be expressed specifically in the brain, and the roles of lncRNAs in neural stem cells (NSCs) and brain development are now beginning to be discovered. Here we review recent advances in understanding the diversity of lncRNA structure and functions in NSCs and brain development. NSCs in the adult mouse ventricular-subventricular zone (V-SVZ) generate new neurons throughout life, and we discuss how key elements of this adult neurogenic system have facilitated the discovery and functional characterization of known and novel lncRNAs. A review of lncRNAs described in other NSC systems reveals a variety of molecular mechanisms, including binding and recruitment of transcription factors, epigenetic modifiers, and RNA-splicing factors. Finally, we review emerging evidence indicating that specific lncRNAs can be key drivers of glial tumors, and discuss next steps towards an in vivo understanding of lncRNA function in development and disease.

Keywords: Brain development; Brain tumor; Cell; Chromatin; Epigenetics; Glioma; Long noncoding RNA; Neural stem; Neurogenesis; lncRNA.

Published by Elsevier Ireland Ltd.

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Figures

Figure 1

Figure 1. The V-SVZ lineage

(A) Coronal view of V-SVZ. (B) Enlarged view of V-SVZ: Type B cells (blue) can contact the ventricle with a thin process extended between ependymal cells (white); type C cells (green) are transit-amplifying cells that give rise to migratory type A cells (red). (C) Sagittal view showing paths of migratory neuroblasts (red, type A cells) to the OB. (D) Schematic of NSC lineages. (E) V-SVZ NSC culture in self-renewal (left) and differentiation (right) conditions. NSCs are GFAP+ (stained in green). Neuroblasts stain for marker Tuj1 (red).

Figure 2

Figure 2. Workflow for identification and characterization of lncRNAs active in neural development

First, unbiased RNA-seq is performed and long noncoding RNA transcripts are reconstructed from these reads. To better characterize gene structure and expression levels, RNA Capture-Seq is performed. LncRNAs (shown here in red) are captured and enriched for further sequencing. ChIP-seq is used to characterize chromatin marks across embryonic stem cells, neural stem cells, and non-neural cell types. Finally, expression profiling is performed using FACS-isolated cells of the V-SVZ lineage. Together these data are integrated to choose candidates for further study. Functional assays performed in vitro include shRNA-mediated knockdown in NSC cultures. To determine lncRNA protein-binding partners, RNA pulldown assays are performed in which biotinylated RNA is mixed with cell extract, followed by pulldown and characterization of bound proteins by mass spectrometry. In vivo models for probing lncRNA function include in utero electroporation of embryonic NSCs, and generation of knockout mouse models.

Figure 3

Figure 3. Knockdown of the lncRNA Pnky enhanced neurogenesis from V-SVZ NSCs

Left: Normal lineage progression of neuronal production from wild-type V-SVZ NSCs (blue) to transit amplifying cells (TA, green) to neuroblasts (NB, red). Pnky is expressed highest in NSCs and becomes down-regulated during lineage progression. Right: Pnky knockdown promotes neuronal production through two mechanisms: 1) a greater proportion of NSCs commit to the neurogenic lineage, and 2) TA cells undergo more cell divisions, resulting in a greater total number of cell divisions and an increased number of “generations” per initial progenitor.

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