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. 2010 Feb 5:11:14.
doi: 10.1186/1471-2202-11-14.

Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation

Tim R Mercer  1 , Irfan A Qureshi, Solen Gokhan, Marcel E Dinger, Guangyu Li, John S Mattick, Mark F Mehler
Affiliations

Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation

Tim R Mercer et al. BMC Neurosci. .

Abstract

Background: Long non-protein-coding RNAs (ncRNAs) are emerging as important regulators of cellular differentiation and are widely expressed in the brain.

Results: Here we show that many long ncRNAs exhibit dynamic expression patterns during neuronal and oligodendrocyte (OL) lineage specification, neuronal-glial fate transitions, and progressive stages of OL lineage elaboration including myelination. Consideration of the genomic context of these dynamically regulated ncRNAs showed they were part of complex transcriptional loci that encompass key neural developmental protein-coding genes, with which they exhibit concordant expression profiles as indicated by both microarray and in situ hybridization analyses. These included ncRNAs associated with differentiation-specific nuclear subdomains such as Gomafu and Neat1, and ncRNAs associated with developmental enhancers and genes encoding important transcription factors and homeotic proteins. We also observed changes in ncRNA expression profiles in response to treatment with trichostatin A, a histone deacetylase inhibitor that prevents the progression of OL progenitors into post-mitotic OLs by altering lineage-specific gene expression programs.

Conclusion: This is the first report of long ncRNA expression in neuronal and glial cell differentiation and of the modulation of ncRNA expression by modification of chromatin architecture. These observations explicitly link ncRNA dynamics to neural stem cell fate decisions, specification and epigenetic reprogramming and may have important implications for understanding and treating neuropsychiatric diseases.

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Figures

Figure 1
Figure 1
Profiles of gene expression during neural stem cell-mediated neural lineage elaboration. (A) Immunofluorescence micrographs of cellular expression patterns of lineage markers and bHLH transcription factors during progressive GABAergic neuronal and OL lineage elaboration from N/OPs: NSCs are labeled with nestin (TRITC) only, while N/OPs (white arrows) express both Olig2 (FITC, green arrow head) and Mash 1 (TRITC, red arrow head). GABANs expressed GABA (FITC). OLPs are stained with O4 (FITC), while PMOs and MYOs are identified by the expression of GC/O1 (FITC) and MBP (FITC), respectively. (B) Schematic flowchart illustrating the stages of oligodendrocyte and GABAergic neuron lineages analyzed within this study. (C) Tree-plot showing expressed ncRNAs clustered according to differential expression during microarray analysis. (D) Expression of mRNA marker genes with well characterized roles in GABAergic neuronal and progressive stages of OL lineage elaboration as determined by microarray.
Figure 2
Figure 2
Detailed examples of ncRNAs expressed during oligodendrocyte differentiation. (A-F) Expression of the ncRNA AK044422 during GABAN and OL differentiation. (A) Genomic context of the ncRNA AK044422 transcript (red), miR-124a (orange), RNA secondary structures as predicted by RNAz [101] (green). (B-E) In situ hybridization of adult mouse brain sagittal sections for AK044422 transcript. (B) AK044422 is expressed broadly throughout the adult mouse brain. (C) AK044422 exhibits an enriched expression in the Cornu Ammonis subfields (CA1-3; blue arrow) (D) Detail of cerebellum shows AK044422 exhibits enriched expression in Purkinje neurons (green arrow). (E) Detail of olfactory bulb shows enriched expression in the mitral layer (red arrow). Images courtesy of (Allen Brain Atlas, http://brain-map.com). (F) Example of RNA secondary structure prediction within AK044422 transcript as rendered by CONTRAfold [99]. (G) Expression of AK044422 (red) and Ptbp1 (blue) according to microarray analysis (expression is relative to NSCs and error bars show standard deviation). (H) Genomic context of Sox8 (blue) and ncRNA Sox8OT transcript (AK070380; red). (I) Expression of Sox8OT (red) and Sox8 (blue) according to microarray analysis. (J) Genomic context of the ncRNAs Neat1 (orange) and Neat2 (dark red) and histogram of vertebrate conservation (dark blue). (K) Expression of Neat1 (orange) and Neat2 (red) according to microarray analysis.
Figure 3
Figure 3
The HDAC inhibitor, TSA prevents the acquisition of secondary morphological features of differentiating PMOs with concurrent alteration in the expression profiles of ncRNAs. (A-D) Immunofluorescence micrographs demonstrating the profiles of OL lineage species in the absence (A, B) or presence of TSA (C, D) at 24 h and 48 h. (E) The fold change in ncRNA expression in TSA treated versus untreated PMOs at 24 h and 48 h. (F) The fold change in Neat1 expression in TSA treated versus untreated PMOs under CNTF presence (instructive) or absence (stochastic) with concurrent PDGF-AA factor withdrawal. Immunofluorescence micrographs of CNTF naïve, TSA treated cells and fold-change as determined by Q-PCR for remaining ncRNAs is illustrated in Additional file 15. (Error bars indicate standard error with asterisks indicated significant fold change at p > 0.05).
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