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Genomic and transcriptional co-localization of protein-coding and long non-coding RNA pairs in the developing brain.

Ponjavic J, Oliver PL, Lunter G, Ponting CP - PLoS Genet. (2009)

Bottom Line: Of this set, those expressed in the brain are more frequently conserved and are significantly enriched with predicted RNA secondary structures.Furthermore, brain-expressed long ncRNAs are preferentially located adjacent to protein-coding genes that are (1) also expressed in the brain and (2) involved in transcriptional regulation or in nervous system development.We provide the full set of constrained long ncRNAs as an important experimental resource and present, for the first time, substantive and predictive criteria for prioritising long ncRNA and mRNA transcript pairs when investigating their biological functions and contributions to development and disease.

View Article: PubMed Central - PubMed

Affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Besides protein-coding mRNAs, eukaryotic transcriptomes include many long non-protein-coding RNAs (ncRNAs) of unknown function that are transcribed away from protein-coding loci. Here, we have identified 659 intergenic long ncRNAs whose genomic sequences individually exhibit evolutionary constraint, a hallmark of functionality. Of this set, those expressed in the brain are more frequently conserved and are significantly enriched with predicted RNA secondary structures. Furthermore, brain-expressed long ncRNAs are preferentially located adjacent to protein-coding genes that are (1) also expressed in the brain and (2) involved in transcriptional regulation or in nervous system development. This led us to the hypothesis that spatiotemporal co-expression of ncRNAs and nearby protein-coding genes represents a general phenomenon, a prediction that was confirmed subsequently by in situ hybridisation in developing and adult mouse brain. We provide the full set of constrained long ncRNAs as an important experimental resource and present, for the first time, substantive and predictive criteria for prioritising long ncRNA and mRNA transcript pairs when investigating their biological functions and contributions to development and disease.

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Adult brain expression patterns of Mitf, Gabrb1, and Add2 overlap with those from ncRNAs transcribed from adjacent genomic sequence.Brightfield images of in situ hybridization from adjacent wild-type adult male 8-week old brain sections are shown. (A) Both Mitf (I) and AK018196 (II) were co-expressed at low levels throughout the brain including the olfactory bulb (data not shown) but also show high levels of expression in the facial nuclei of the medulla. (B) Gabrb1 (I) and AK045528 (II) are co-expressed in most brain regions (data not shown), including specifically around the Purkinje cell layer of the cerebellum. (C) Add2 (I) and AK013768 (II) are also expressed in all areas of the brain, but levels are substantially higher in the hippocampus in both cases. (A, B, C) The sense strand probe from the corresponding protein-coding gene is shown (III). Scale bars represent 0.25 mm (A, B III) and 0.5 mm (C III). No expression information regarding any of these ncRNAs is currently available from the Allen Brain Atlas [23]. Column IV represents the genomic landscape for each protein-coding (light blue) and non-coding (red) transcript pair. Experimental evidence for transcription in the form of CAGE tag clusters (TC) (orange) [1],[18] and EST (green) data are also represented (as modified from the FANTOM3 Mouse Genomic Element Viewer (http://fantom32p.gsc.riken.jp/gev-f3/gbrowse/mm5): only unique transcripts and ESTs are shown). The size of a TC reflects the number of CAGE tags that are mapped to this region. A TC and its surrounding genomic sequence together can be considered a core promoter. It is evident that all three ncRNAs have further experimental support from ESTs (including those that are unspliced) and CAGE TCs (also listed in Table S4). AK045528 and AK013768 ncRNA transcripts are overlapped by ESTs and CAGE TCs that are derived from brain-associated tissues from adult and developing mice, whereas AK018196 has support from adult mouse brain ESTs.
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pgen-1000617-g006: Adult brain expression patterns of Mitf, Gabrb1, and Add2 overlap with those from ncRNAs transcribed from adjacent genomic sequence.Brightfield images of in situ hybridization from adjacent wild-type adult male 8-week old brain sections are shown. (A) Both Mitf (I) and AK018196 (II) were co-expressed at low levels throughout the brain including the olfactory bulb (data not shown) but also show high levels of expression in the facial nuclei of the medulla. (B) Gabrb1 (I) and AK045528 (II) are co-expressed in most brain regions (data not shown), including specifically around the Purkinje cell layer of the cerebellum. (C) Add2 (I) and AK013768 (II) are also expressed in all areas of the brain, but levels are substantially higher in the hippocampus in both cases. (A, B, C) The sense strand probe from the corresponding protein-coding gene is shown (III). Scale bars represent 0.25 mm (A, B III) and 0.5 mm (C III). No expression information regarding any of these ncRNAs is currently available from the Allen Brain Atlas [23]. Column IV represents the genomic landscape for each protein-coding (light blue) and non-coding (red) transcript pair. Experimental evidence for transcription in the form of CAGE tag clusters (TC) (orange) [1],[18] and EST (green) data are also represented (as modified from the FANTOM3 Mouse Genomic Element Viewer (http://fantom32p.gsc.riken.jp/gev-f3/gbrowse/mm5): only unique transcripts and ESTs are shown). The size of a TC reflects the number of CAGE tags that are mapped to this region. A TC and its surrounding genomic sequence together can be considered a core promoter. It is evident that all three ncRNAs have further experimental support from ESTs (including those that are unspliced) and CAGE TCs (also listed in Table S4). AK045528 and AK013768 ncRNA transcripts are overlapped by ESTs and CAGE TCs that are derived from brain-associated tissues from adult and developing mice, whereas AK018196 has support from adult mouse brain ESTs.

Mentions: Similarly, at random, we chose an additional 6 protein-coding and non-coding pairs for which the ncRNA was initially identified in the brains of adult mice. Available data [23] also indicate expression for each of these 6 protein-coding genes within the specific sub-region of the adult brain from which its partner ncRNA transcript was originally derived. Of the 6 adult-expressed protein-coding gene partners, all were detectable in the brain by in situ hybridisation; of these, the expression patterns of 5 overlapped with those of their adjacent non-coding RNAs (Figure 6 and Figure S3).


Genomic and transcriptional co-localization of protein-coding and long non-coding RNA pairs in the developing brain.

Ponjavic J, Oliver PL, Lunter G, Ponting CP - PLoS Genet. (2009)

Adult brain expression patterns of Mitf, Gabrb1, and Add2 overlap with those from ncRNAs transcribed from adjacent genomic sequence.Brightfield images of in situ hybridization from adjacent wild-type adult male 8-week old brain sections are shown. (A) Both Mitf (I) and AK018196 (II) were co-expressed at low levels throughout the brain including the olfactory bulb (data not shown) but also show high levels of expression in the facial nuclei of the medulla. (B) Gabrb1 (I) and AK045528 (II) are co-expressed in most brain regions (data not shown), including specifically around the Purkinje cell layer of the cerebellum. (C) Add2 (I) and AK013768 (II) are also expressed in all areas of the brain, but levels are substantially higher in the hippocampus in both cases. (A, B, C) The sense strand probe from the corresponding protein-coding gene is shown (III). Scale bars represent 0.25 mm (A, B III) and 0.5 mm (C III). No expression information regarding any of these ncRNAs is currently available from the Allen Brain Atlas [23]. Column IV represents the genomic landscape for each protein-coding (light blue) and non-coding (red) transcript pair. Experimental evidence for transcription in the form of CAGE tag clusters (TC) (orange) [1],[18] and EST (green) data are also represented (as modified from the FANTOM3 Mouse Genomic Element Viewer (http://fantom32p.gsc.riken.jp/gev-f3/gbrowse/mm5): only unique transcripts and ESTs are shown). The size of a TC reflects the number of CAGE tags that are mapped to this region. A TC and its surrounding genomic sequence together can be considered a core promoter. It is evident that all three ncRNAs have further experimental support from ESTs (including those that are unspliced) and CAGE TCs (also listed in Table S4). AK045528 and AK013768 ncRNA transcripts are overlapped by ESTs and CAGE TCs that are derived from brain-associated tissues from adult and developing mice, whereas AK018196 has support from adult mouse brain ESTs.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2722021&req=5

pgen-1000617-g006: Adult brain expression patterns of Mitf, Gabrb1, and Add2 overlap with those from ncRNAs transcribed from adjacent genomic sequence.Brightfield images of in situ hybridization from adjacent wild-type adult male 8-week old brain sections are shown. (A) Both Mitf (I) and AK018196 (II) were co-expressed at low levels throughout the brain including the olfactory bulb (data not shown) but also show high levels of expression in the facial nuclei of the medulla. (B) Gabrb1 (I) and AK045528 (II) are co-expressed in most brain regions (data not shown), including specifically around the Purkinje cell layer of the cerebellum. (C) Add2 (I) and AK013768 (II) are also expressed in all areas of the brain, but levels are substantially higher in the hippocampus in both cases. (A, B, C) The sense strand probe from the corresponding protein-coding gene is shown (III). Scale bars represent 0.25 mm (A, B III) and 0.5 mm (C III). No expression information regarding any of these ncRNAs is currently available from the Allen Brain Atlas [23]. Column IV represents the genomic landscape for each protein-coding (light blue) and non-coding (red) transcript pair. Experimental evidence for transcription in the form of CAGE tag clusters (TC) (orange) [1],[18] and EST (green) data are also represented (as modified from the FANTOM3 Mouse Genomic Element Viewer (http://fantom32p.gsc.riken.jp/gev-f3/gbrowse/mm5): only unique transcripts and ESTs are shown). The size of a TC reflects the number of CAGE tags that are mapped to this region. A TC and its surrounding genomic sequence together can be considered a core promoter. It is evident that all three ncRNAs have further experimental support from ESTs (including those that are unspliced) and CAGE TCs (also listed in Table S4). AK045528 and AK013768 ncRNA transcripts are overlapped by ESTs and CAGE TCs that are derived from brain-associated tissues from adult and developing mice, whereas AK018196 has support from adult mouse brain ESTs.
Mentions: Similarly, at random, we chose an additional 6 protein-coding and non-coding pairs for which the ncRNA was initially identified in the brains of adult mice. Available data [23] also indicate expression for each of these 6 protein-coding genes within the specific sub-region of the adult brain from which its partner ncRNA transcript was originally derived. Of the 6 adult-expressed protein-coding gene partners, all were detectable in the brain by in situ hybridisation; of these, the expression patterns of 5 overlapped with those of their adjacent non-coding RNAs (Figure 6 and Figure S3).

Bottom Line: Of this set, those expressed in the brain are more frequently conserved and are significantly enriched with predicted RNA secondary structures.Furthermore, brain-expressed long ncRNAs are preferentially located adjacent to protein-coding genes that are (1) also expressed in the brain and (2) involved in transcriptional regulation or in nervous system development.We provide the full set of constrained long ncRNAs as an important experimental resource and present, for the first time, substantive and predictive criteria for prioritising long ncRNA and mRNA transcript pairs when investigating their biological functions and contributions to development and disease.

View Article: PubMed Central - PubMed

Affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Besides protein-coding mRNAs, eukaryotic transcriptomes include many long non-protein-coding RNAs (ncRNAs) of unknown function that are transcribed away from protein-coding loci. Here, we have identified 659 intergenic long ncRNAs whose genomic sequences individually exhibit evolutionary constraint, a hallmark of functionality. Of this set, those expressed in the brain are more frequently conserved and are significantly enriched with predicted RNA secondary structures. Furthermore, brain-expressed long ncRNAs are preferentially located adjacent to protein-coding genes that are (1) also expressed in the brain and (2) involved in transcriptional regulation or in nervous system development. This led us to the hypothesis that spatiotemporal co-expression of ncRNAs and nearby protein-coding genes represents a general phenomenon, a prediction that was confirmed subsequently by in situ hybridisation in developing and adult mouse brain. We provide the full set of constrained long ncRNAs as an important experimental resource and present, for the first time, substantive and predictive criteria for prioritising long ncRNA and mRNA transcript pairs when investigating their biological functions and contributions to development and disease.

Show MeSH
Related in: MedlinePlus