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. 2012 Aug;9(8):1054-65.
doi: 10.4161/rna.21082. Epub 2012 Aug 1.

Spatio-temporal regulation of ADAR editing during development in porcine neural tissues

Morten T Venø  1 , Jesper B Bramsen, Christian Bendixen, Frank Panitz, Ida Elisabeth Holm, Marie Öhman, Jørgen Kjems
Affiliations

Spatio-temporal regulation of ADAR editing during development in porcine neural tissues

Morten T Venø et al. RNA Biol. 2012 Aug.

Abstract

Editing by ADAR enzymes is essential for mammalian life. Still, knowledge of the spatio-temporal editing patterns in mammals is limited. By use of 454 amplicon sequencing we examined the editing status of 12 regionally extracted mRNAs from porcine developing brain encompassing a total of 64 putative ADAR editing sites. In total 24 brain tissues, dissected from up to five regions from embryonic gestation day 23, 42, 60, 80, 100 and 115, were examined for editing. Generally, editing increased during embryonic development concomitantly with an increase in ADAR2 mRNA level. Notably, the Gria2 (GluR-B) Q/R site, reported to be ~100% edited in previous studies, is only 54% edited at embryonic day 23. Transcripts with multiple editing sites in close proximity to each other exhibit coupled editing and an extraordinary incidence of long-range coupling of editing events more than 32 kb apart is observed for the kainate glutamate receptor 2 transcript, Grik2. Our study reveals complex spatio-temporal ADAR editing patterns of coordinated editing events that may play important roles in the development of the mammalian brain.

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Figures

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Figure 1. Mean editing and ADAR2 mRNA expression. (A) Mean editing of ADAR edited transcripts displaying at least 10% editing as a function of embryonic development. The mean editing of transcripts across all brain regions examined is indicated in percentage based on measurement at the indicated gestation time points. (B) The mean ADAR2 mRNA expression level relative to GAPDH averaged across all brain regions at the indicated gestation time points.
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Figure 2. Editing level for Grik2 editing sites (A-C) and the three primary ADAR2 self-editing sites (D-F) at different gestation time points. The color code refers to tissue type and is indicated below the figure. Note that only one tissue, whole forebrain, was dissected from E23 due to the small size of the embryo at this stage.
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Figure 3. Editing level for the Gria2 Q/R site (A) and all the 5 Htr2c sites (B-F) indicated in percentages. Note that only one tissue, whole forebrain, was dissected from E23.
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Figure 4. Coupling of editing events for Htr2c and Blcap transcripts. (A) Pearson correlation coefficients for coupling between all editing sites on the Htr2c amplicon in cortex. See legend for color codes. Black asterisks denote significance compared with bonferroni corrected critical p values. (B) Group analysis of all cortex E115 Htr2c editing sites. (C) The genomic nucleotide sequence immediately surrounding the editing sites in Htr2c (A, B, C', C and D) and the sequence of the corresponding cDNA with edited nucleotides depicted in red. The genomically coded amino acid sequence is shown in black and the resulting amino acids after editing are shown in red. (D) Pearson correlation coefficients for coupling between the predominant editing sites on the Blcap amplicon in cortex. See legend for color codes. Black asterisks denote significance compared with bonferroni corrected critical p values. (E) Group analysis of cortex E115 Blcap editing sites. (F) Schematic drawing (not to scale) of the editing sites (red asterisks) in Blcap showing the three editing sites in 5′UTR region (thin line; 5a, 5b, 5c) and the five editing sites inside the coding region (open box) detected in this study. Note that only one tissue, whole forebrain, was dissected from E23.
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Figure 5. Coupling of editing events for ADAR2 and Grik2 transcripts. (A) Pearson correlation coefficients for coupling between the predominant self-editing sites on the ADAR2 amplicon in cortex. See legend for color codes. Black asterisks denote significance compared with bonferroni corrected critical p values. (B) Group analysis of all cortex E115 ADAR2 self-editing sites. (C) Schematic drawing (not to scale) of the editing sites detected in ADAR2 (red asterisks). The entire depicted region is intronic in the unedited pre-mRNA but editing of the -1 site causes inclusion of the open boxed section in the downstream exon. (D) Pearson correlation coefficients for coupling between all editing sites on the Grik2 amplicon in cortex. See legend for color codes. Black asterisks denote significance compared with bonferroni corrected critical p values. (E) Group analysis of all cortex E115 Grik2 editing sites. (F) Schematic drawing (not to scale) of the editing sites in Grik2 showing the five editing sites (red asterisks) detected in this study. I/V and Y/C sites are separated from G/G, M/V and Q/R sites by a 32 kb intron. Note that only one tissue, whole forebrain, was dissected from E23.
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Figure 6. Tertiary modeling of the edited regions of the Blcap (A and B), Htr2c (C and D) and ADAR2 (E and F) pre-mRNAs with intronic ECS. The tertiary models are shown from the side (A, C and E) and head-on (B, D and F). Red spheres are editing sites displaying coupling. Light red spheres are uncoupled editing sites.
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