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

2017; Cell Press; Volume: 21; Issue: 1 Linguagem: Inglês

10.1016/j.celrep.2017.09.014

2639-1856

Marilyn Scandaglia, José P. López‐Atalaya, Francisco J. Medrano, María T. Lopez-Cascales, Beatriz del Blanco, Michał Lipiński, Eva Benito, Román Olivares, Shigeki Iwase, Yang Shi, Ángel Barco,

Genomics and Chromatin Dynamics

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.