Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons
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 develo...
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doaj-0c9ba7d748a641f39fbdc4c38cf5460e2020-11-24T23:54:39ZengElsevierCell Reports2211-12472017-10-01211475910.1016/j.celrep.2017.09.014Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in NeuronsMarilyn Scandaglia0Jose P. Lopez-Atalaya1Alejandro Medrano-Fernandez2Maria T. Lopez-Cascales3Beatriz del Blanco4Michal Lipinski5Eva Benito6Roman Olivares7Shigeki Iwase8Yang Shi9Angel Barco10Instituto 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, SpainInstituto 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, SpainInstituto 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, SpainInstituto 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, SpainInstituto 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, SpainInstituto 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, SpainInstituto 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, SpainInstituto 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, SpainDepartment of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI 48109, USADivision of Newborn Medicine, Boston Children’s Hospital, Boston, MA 02115, USAInstituto 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, SpainDuring 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.http://www.sciencedirect.com/science/article/pii/S2211124717312755intellectual disabilityClaes-Jensen syndromelysine demethylase 5Chistone methylationspurious transcriptiongermline gene silencingimmediate early geneenhancerepigenetic repressionDNA methylation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons Cell Reports intellectual disability Claes-Jensen syndrome lysine demethylase 5C histone methylation spurious transcription germline gene silencing immediate early gene enhancer epigenetic repression DNA methylation |
author_facet |
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 |
author_sort |
Marilyn Scandaglia |
title |
Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons |
title_short |
Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons |
title_full |
Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons |
title_fullStr |
Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons |
title_full_unstemmed |
Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons |
title_sort |
loss of kdm5c causes spurious transcription and prevents the fine-tuning of activity-regulated enhancers in neurons |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2017-10-01 |
description |
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. |
topic |
intellectual disability Claes-Jensen syndrome lysine demethylase 5C histone methylation spurious transcription germline gene silencing immediate early gene enhancer epigenetic repression DNA methylation |
url |
http://www.sciencedirect.com/science/article/pii/S2211124717312755 |
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