Scandaglia, Marilyn, Lopez-Atalaya, Jose P., Medrano-Fernandez, Alejandro, Lopez-Cascales, Maria T., del Blanco, Beatriz, Lipinski, Michal, Benito, Eva, Olivares, Roman, Iwase, Shigeki, Shi, Yang, and Barco, Angel
Summary During development, chromatin-modifying enzymes regulate both the timely establishment of cell-type-specific gene programs and the coordinated repression of alternative cell fates. To dissect the role of one such enzyme, the intellectual-disability-linked lysine demethylase 5C (Kdm5c), in the developing and adult brain, we conducted parallel behavioral, transcriptomic, and epigenomic studies in Kdm5c -null and forebrain-restricted inducible knockout mice. Together, genomic analyses and functional assays demonstrate that Kdm5c plays a critical role as a repressor responsible for the developmental silencing of germline genes during cellular differentiation and in fine-tuning activity-regulated enhancers during neuronal maturation. Although the importance of these functions declines after birth, Kdm5c retains an important genome surveillance role preventing the incorrect activation of non-neuronal and cryptic promoters in adult neurons. [ABSTRACT FROM AUTHOR]