Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons

• Main Authors: Marilyn Scandaglia, Jose P. Lopez-Atalaya, Alejandro Medrano-Fernandez, Maria T. Lopez-Cascales, Beatriz del Blanco, Michal Lipinski, Eva Benito, Roman Olivares, Shigeki Iwase, Yang Shi, Angel Barco
• Format: Article
• Language: English
• Published: Elsevier 2017-10-01
• Series: Cell Reports
• Subjects: intellectual disability; Claes-Jensen syndrome; lysine demethylase 5C; histone methylation; spurious transcription; germline gene silencing; immediate early gene; enhancer; epigenetic repression; DNA methylation
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124717312755

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.