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

Publication date: 3 October 2017
Source:Cell Reports, Volume 21, Issue 1
Author(s): 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
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.

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Teaser

Scandaglia et al. show that Kdm5c plays critical roles constraining transcription during neuronal differentiation and maturation. Although Kdm5c contribution to neuronal transcription regulation later declines, it retains a genome surveillance role precluding spurious transcription in adult neurons. These functions likely contribute to the pathoetiology of Claes-Jensen-type X-linked intellectual disability.


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