Genome-wide analysis of enhancers repressed by Nkx2.2 in spinal motor neuron progenitors

ABSTRACT: Unambiguous consolidation of cell identity relies on transcription factors (TFs) acting to suppress alternative lineages, yet few general principles have emerged explaining how repressors manipulate chromatin landscapes to achieve stable gene silencing, especially in instances when these TFs are only temporarily activated. The TF Nkx2.2 is transiently expressed in CNS progenitors yet permanently abrogates somatic motor neuron (sMN) differentiation via interactions with Groucho (Grg) co-repressors. We show that Nkx2.2 inhibits regulatory elements of progenitor and postmitotic sMN transcripts by utilizing Grg to evict co-activators. Surprisingly, co-activator eviction was accomplished using Grg proteins already present at enhancers, rather than through the additional recruitment of Grg or other co-repressors. Nkx2.2-mediated enhancer silencing also led to the loss of H3K27ac modifications from H3K27me3+H3K27ac+ proximal promoters of key sMN genes, facilitating persistent repression of the sMN progenitor program after Nkx2.2 downregulation. These results imply that active loci are poised for suppression, and repressor binding mediates the transition through co-activator displacement.

ORGANISM(S): Mus musculus

PROVIDER: GSE155229 | GEO | 2023/07/24

REPOSITORIES: GEO