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Cell Rep. 2017 Oct 3;21(1):47-59. doi: 10.1016/j.celrep.2017.09.014.

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

Author information

1
Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Molecular Neurobiology and Neuropathology Unit, Av. Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain.
2
Department of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI 48109, USA.
3
Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
4
Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Molecular Neurobiology and Neuropathology Unit, Av. Santiago Ramón y Cajal s/n, Sant Joan d'Alacant, 03550 Alicante, Spain. Electronic address: abarco@umh.es.

Abstract

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.

KEYWORDS:

Claes-Jensen syndrome; DNA methylation; enhancer; epigenetic repression; germline gene silencing; histone methylation; immediate early gene; intellectual disability; lysine demethylase 5C; spurious transcription

PMID:
28978483
PMCID:
PMC5679733
DOI:
10.1016/j.celrep.2017.09.014
[Indexed for MEDLINE]
Free PMC Article

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