Abstract
Long non-coding RNAs (lncRNAs) (> 200 bp) play crucial roles in transcriptional regulation during numerous biological processes. However, it is challenging to comprehensively identify lncRNAs, because they are often expressed at low levels and with more cell-type specificity than are protein-coding genes. In the present study, we performed ab initio transcriptome reconstruction using eight purified cell populations from mouse cortex and detected more than 5000 lncRNAs. Predicting the functions of lncRNAs using cell-type specific data revealed their potential functional roles in Central Nervous System (CNS) development. We performed motif searches in ENCODE DNase I digital footprint data and Mouse ENCODE promoters to infer transcription factor (TF) occupancy. By integrating TF binding and cell-type specific transcriptomic data, we constructed a novel framework that is useful for systematically identifying lncRNAs that are potentially essential for brain cell fate determination. Based on this integrative analysis, we identified lncRNAs that are regulated during Oligodendrocyte Precursor Cell (OPC) differentiation from Neural Stem Cells (NSCs) and that are likely to be involved in oligodendrogenesis. The top candidate, lnc-OPC, shows highly specific expression in OPCs and remarkable sequence conservation among placental mammals. Interestingly, lnc-OPC is significantly up-regulated in glial progenitors from experimental autoimmune encephalomyelitis (EAE) mouse models compared to wild-type mice. OLIG2-binding sites in the upstream regulatory region of lnc-OPC were identified by ChIP (chromatin immunoprecipitation)-Sequencing and validated by luciferase assays. Loss-of-function experiments confirmed that lnc-OPC plays a functional role in OPC genesis. Overall, our results substantiated the role of lncRNA in OPC fate determination and provided an unprecedented data source for future functional investigations in CNS cell types. We present our datasets and analysis results via the interactive genome browser at our laboratory website that is freely accessible to the research community. This is the first lncRNA expression database of collective populations of glia, vascular cells, and neurons. We anticipate that these studies will advance the knowledge of this major class of non-coding genes and their potential roles in neurological development and diseases.
Highlights
More than 98% of the human genome does not encode proteins
Between 70 and 90% of the mammalian genome is transcribed at some point during development; only < 2% of the genome is associated with protein-coding genes
By integrating differential gene expression and transcription factor occupancy information, long non-coding RNAs (lncRNAs) that are likely involved in oligodendrocyte precursor cell formation were identified
Summary
More than 98% of the human genome does not encode proteins. Thousands of long non-coding RNAs (lncRNAs: usually > 200 bp in length, often spliced and polyadenylated, but lacking protein-coding potential) were recently discovered and many of them have been shown to play crucial roles in diverse biological processes [6, 7]. Emerging evidence indicates that lncRNAs may have important roles in Central Nervous System (CNS) development, homeostasis, stress responses, and plasticity [6]. Many lncRNAs are expressed in the mouse brain and show regionspecific expression patterns [8]. Many lncRNAs exhibit dynamic expression patterns during neuronal-glial fate specification and oligodendrocyte lineage maturation [6]. LncRNAs have been shown to be involved in some neuropsychiatric diseases [9]
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