Fig. 5: m6A is dysregulated in HD. | Nature Neuroscience

Fig. 5: m6A is dysregulated in HD.

From: Aberrant splicing in Huntington’s disease accompanies disrupted TDP-43 activity and altered m6A RNA modification

Fig. 5

a, Representative images showing modest decrease in Mettl3 signal in the R6/2 cortex and striatum. b, CellProfiler analysis of Mettl3 nuclear intensity; statistical significance was determined by unpaired two-tailed t-test (cortex: P = 0.0184, t = 2.693, d.f. = 13, F = 1.572, 95% CI: −0.1158 to −0.01270; striatum: P = 0.0093, t = 3.052, d.f. = 13, F = 1.044, 95% CI: −0.0774 to −0.0324). n = 8 (four males, four females) per genotype were quantified, each averaging three cortical or striatal regions. Data are presented as mean values ± s.e.m. c, MS for m6A showed no significant changes by unpaired two-tailed t-test (P = 0.0567, t = 1.982, d.f. = 30) in global m6A levels. Data are presented as mean values ± s.e.m. n = 16 per genotype (five males, 11 females). d, Violin plots showing increased m6A sites per gene on genes that are dysregulated in HD R6/2 (DEGs), in particular in downregulated genes compared to upregulated genes. Statistical significance was determined by unpaired two-tailed t-test. DEGs versus non-DEGs: P < 0.0001, t = 15.03, d.f. = 3818, F = 3.099, 95% CI: −9.075 to −6.981; Up versus Down: P < 0.0001, t = 11.52, d.f. = 3384, F = 2.870, 95% CI: 5.688–8.021. e, m6A site deposition (localized levels) on 266 genes dysregulated in R6/2 striatum. f, Histogram plot showing TDP-43 eCLIP sites relative to an m6A site (from m6A eCLIP data) (0 position) compared to Hnrnp C and Hnrnp L binding motifs. g, m6A site deposition (localized levels) on 266 genes dysregulated with TDP-43 KD by ASO. h, Representative images showing significant increase in m6A IF intensity in HD patient caudate nucleus (CN) with corresponding METTL3 staining. Dot plot with each dot representing the average m6A intensity per neuronal cell spanning five ×20 confocal images per patient (three controls, six HD). Samples were grouped to either control or HD group with the unpaired Studentʼs t-test for significance (for separated dot plots, see Supplementary Fig. 7g) (P < 0.0001, t = 13.82, d.f. = 956, F = 3.313, 95% CI: 0.09684–0.1289). Bar represents the median. Experiments in a, b and h were repeated at least three times with similar results represented above.

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