Fig. 3: SETD1A targets active promoter regions of common SCZ risk genes, regulating chromatin remodeling, DNA repair, and synaptic signaling pathways in human brain development. | Nature Communications

Fig. 3: SETD1A targets active promoter regions of common SCZ risk genes, regulating chromatin remodeling, DNA repair, and synaptic signaling pathways in human brain development.

From: SETD1A regulates psychiatric gene networks involved in genomic stability and synaptic function in rare and sporadic schizophrenia

Fig. 3: SETD1A targets active promoter regions of common SCZ risk genes, regulating chromatin remodeling, DNA repair, and synaptic signaling pathways in human brain development.The alternative text for this image may have been generated using AI.

a Schematic of brain tissue dissected and Allen Human Brain Atlas image at post-conception week (PCW) 21 https:/atlas.brain-map.org/atlas?atlas=3#atlas=3&plate=101892621&structure=11585&x=10116&y=23872&zoom=-7&resolution=128.08&z=372&zoom=-7&resolution=128.08&z=3. Human prenatal cortices were dissected to include ventricular zone through marginal zone. b Proportion of SETD1A peaks at active promoters in human prenatal cortices and isogenic iPSC-derived NPCs and neurons. c Representative IGV tracks of CUT&Tag signals for H3K4me3, SETD1A_CST, SETD1A_Atlas, and control IgG on chr16. Black bars indicate peaks at active promoters. d Overrepresentation of SETD1A peaks in human prenatal cortices and isogenic iPSC-derived NPCs and neurons on 287 SCZ GWAS loci5. Permutation test, ****p < 0.0001. e LDSC analysis showing heritability enrichment for psychiatric disorders (SCZ, BD, MDD), neurodevelopmental disorders (ASD, ADHD), neurodegenerative disorders (AD, PD), stroke, and T2DM across SETD1A binding sites. *p < 0.05; ***p < 0.001; ****p < 0.0001. f GO:BP terms enriched for SCZ GWAS significant genes with SETD1A-bound active promoters in human prenatal cortices (165 genes), WT NPCs (199 genes) and WT neurons (199 genes) among 682 SCZ GWAS significant genes5. *FDR < 0.05; **FDR < 0.01; ***FDR < 0.001; ****FDR < 0.0001. g Comparison of SETD1A peaks at active promoters between genotypes (one WT and one SETD1Ac.4582-2delAG/+ lines with technical duplicates for NPCs; two WT and two SETD1Ac.4582-2delAG/+ lines for neurons). Unpaired t-test, **p = 0.0085; n.s. not significant. h Venn diagram showing overlap of SETD1A peaks at active promoters between genotypes. Numbers indicate peak counts; parentheses indicate annotated gene counts. Red parentheses indicate SCZ GWAS-significant genes. i Representative IGV tracks showing lost SETD1A binding in SETD1Ac.4582-2delAG/+ cells (dashed boxes). j Comparison of SETD1A and H3K4me3 binding densities at lost/gained regions. Wilcoxon signed-rank test, ***p = 0.00012; ****p < 0.0001. k GO:BP terms enriched in genes with lost promoter regions and enrichment of 116 SCZ GWAS significant genes. *FDR < 0.05; **FDR < 0.01; ***FDR < 0.001; ****FDR < 0.0001. l Expression of 116 SCZ GWAS significant genes with lost promoter regions. Wilcoxon signed-rank test, ****p < 0.0001. Data presented as mean ± S.E.M. (b), mean ± S.D. (g), median with 25th–75th percentiles and min-max whiskers (j, l). All tests two-sided. RPKM reads per kilobase per million, TPM transcripts per million.

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