CREST functions as a molecular bridge between neuron-specific enhancers and epigenetic regulators in mature motor neurons

ABSTRACT: Neuronal cell identity is partially established by epigenetic regulatory proteins, including chromatin remodeling complexes, which use their ATPase to modulate the accessibility of cis-regulatory DNA elements such as enhancers. Neuron-specific BAF (Brg1/Brm-associated factor) chromatin remodeling complexes contain a non-catalytic subunit, CREST, whose de novo mutations have been identified in motor neuron disease patients. However, the mechanisms by which CREST regulates neuronal gene expression programs during motor neuron differentiation remain unclear. Here, we elucidate the genome-wide mechanisms by which CREST regulates motor neuron differentiation from mouse embryonic stem cells. We found that CREST recognizes enhancers bound by motor neuron-specific transcription factors Onecut1 and Ngn2. Then, CREST selectively recruits the CBP histone acetyltransferase to acetylate histone H3 lysine 27 at neuronal enhancers, leading to the epigenetic activation of mature neuronal genes through long-range chromatin interactions. We also show that CREST-bound enhancers gain accessibility through selective recruitment of the neuron-specific Brm ATPase during the transition from neural progenitors to mature motor neurons. Furthermore, CREST knockout disrupts the expression of other subunits of neuronal BAF chromatin remodeling complexes, suggesting that CREST may influence the assembly of these complexes. Our findings reveal a non-canonical role of neuron-specific chromatin remodeling factors, demonstrating that CREST mediates communication between epigenetic regulators and neuron-specific enhancers, which are essential for proper neuronal function.

ORGANISM(S): Mus musculus

PROVIDER: GSE326223 | GEO | 2026/08/20

REPOSITORIES: GEO