Figure 4.

BCL11B-regulated transcription programs in MSNs and CTX neurons overlap with mHTT–coregulated pathways. (A) Kyoto Encyclopedia of Genes and Genomes and Ingenuity Pathway Analysis of differentially expressed genes at false discovery rate p_adj < .01 shows a significant enrichment of genes regulating cAMP-PKA-calcium signaling axis and synaptic signaling in both neuron types as well as DA-DARPP32 signaling specifically in MSNs (full gene set lists are presented in Table S2). (B) BCL11B target genes within shortlisted core biological processes affected by the loss of BCL11B in MSN and CTX neurons. Next to gene name, color icons indicate significant association (differential expression or identified risk variant) with HD (pink), SCZ (green), NDD (blue), and ASD (yellow). (C) Exclusion of BCL11B target genes from differentially expressed gene list results in several pathways in MSNs becoming either drastically less significant or not significant at all, including cAMP-PKA-calcium signaling axis pathways and dopamine synapse signaling, while having almost no effect on signaling pathways in CTX neurons. (D) BCL11B-regulated signaling abnormalities in MSNs and CTX neurons are shared by HD neurons (full gene set lists are presented in Table S4). In pathway graphs (A, D), dot size corresponds to gene set size, dot color corresponds to −log₁₀(pval), where p_adj < .05 dot is framed inside a black circle. See also Figures S5 and S6 and Tables S1–S4. ASD, autism spectrum disorder; BDNF, brain-derived neurotrophic factor; CTX, cortical glutamatergic; DA, dopamine; excl., exclusion; GABA, gamma-aminobutyric acid; HD, Huntington’s disease; incl., inclusion; mHTT, mutant huntingtin; MSNs, medium spiny neurons; NDD, neurodevelopmental disorder; p_adj, p adjusted; PKA, protein kinase A; SCZ, schizophrenia.