Aberrant homeodomain–DNA cooperative dimerization underlies distinct developmental defects in two dominant CRX retinopathy models

Differential HD motif usage in photoreceptor development and diseases. (A) Q₅₀ and K₅₀ paired-class HDs prefer different monomeric and dimeric DNA motifs. (B,C) In postnatal photoreceptor precursors, regulatory elements with Q₅₀ HD motifs are gradually closed (silenced) owing to a lack of interacting TFs. High-affinity monomeric K₅₀ HD motifs respond to low concentration of CRX, drive chromatin remodeling in early-stage development, and plateau in their regulatory output at a later stage. Dimeric K₅₀ HD motifs of individually low-affinity half-sites respond at high CRX concentration and are associated with chromatin remodeling and gene expression regulation at photoreceptor terminal differentiation. (D) In Crx^K88N mutant retinas, CRX^K88N’s ectopic binding impedes the silencing of regulatory elements with Q₅₀ HD motifs. In Crx^E80A mutant retinas, CRX^E80A’s enhanced interactions with monomeric K₅₀ HD motifs and defective cooperative binding at dimeric K₅₀ HD motifs lead to accelerated chromatin remodeling in early-stage development but defective remodeling at terminal differentiation stage. (dLCA) Dominant Leber congenital amaurosis, (dCoRD) dominant cone-rod dystrophy.