Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons
| Autor: | Yang Shi, Román Olivares, Marilyn Scandaglia, José P. López-Atalaya, Beatriz del Blanco, Michal Lipinski, Alejandro Medrano-Fernandez, Shigeki Iwase, María T. Lopez-Cascales, Eva Benito, Angel Barco |
|---|---|
| Přispěvatelé: | Ministerio de Economía y Competitividad (España), European Commission, Generalitat Valenciana, Brain and Behavior Research Foundation, Fundación Alicia Koplowitz, National Institutes of Health (US) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Doublecortin Domain Proteins Male Transcription Genetic Cellular differentiation spurious transcription Histones Mice 0302 clinical medicine lysine demethylase 5C lcsh:QH301-705.5 Epigenomics Genetics Histone Demethylases Mice Knockout Neurons DNA methylation Gene Expression Regulation Developmental Nuclear Proteins DNA-Binding Proteins Enhancer Elements Genetic intellectual disability Female Microtubule-Associated Proteins Signal Transduction immediate early gene epigenetic repression Nerve Tissue Proteins Biology General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences germline gene silencing Prosencephalon Glial Fibrillary Acidic Protein Gene silencing Animals histone methylation Enhancer Maze Learning Gene Psychological repression Claes-Jensen syndrome Neuropeptides Oxidoreductases N-Demethylating 030104 developmental biology lcsh:Biology (General) Epigenetic Repression biology.protein Demethylase enhancer 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 21, Iss 1, Pp 47-59 (2017) Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid |
| ISSN: | 2211-1247 |
| Popis: | 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. M.S. and A.M.-F. are recipients of “Formación de Personal Investigador” fellowships, and B.d.B. is the recipient of a “Juan de la Cierva – Incorporación” contract (all from the Spanish Ministry of Economy and Competitivity [MINECO]). J.P.L.-A.’s research is supported by a “Ramón y Cajal” contract and by grant SAF2014-60233-JIN from MINECO (co-financed by the European Regional Development Fund [ERDF]). A.B.’s research is supported by grants SAF2014-56197-R, PCIN-2015-192-C02-01 (part of the coordinated project ERA-Net NEURON8-2015), and SEV-2013-0317 from MINECO (co-financed by ERDF), grant PROMETEO/2016/006 from the Generalitat Valenciana, a NARSAD Independent Investigator grant (no. 21941) from the Brain & Behavior Research Foundation, and a grant from the Alicia Koplowitz Foundation. S.I.’s research is supported by NIH grant NS089896 and the Farrehi Family Foundation. KDM5C research in the Y.S. lab is supported by NIH grant MH096066. Y.S. is an American Cancer Society Research Professor. The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa.” |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|