TY - JOUR
T1 - The REST remodeling complex protects genomic integrity during embryonic neurogenesis
AU - Nechiporuk, Tamilla
AU - McGann, James
AU - Mullendorff, Karin
AU - Hsieh, Jenny
AU - Wurst, Wolfgang
AU - Floss, Thomas
AU - Mandel, Gail
N1 - Funding Information:
The following grants supported this work: NIH grant NS22518 to GM; Bayerische Staatsministerium f?r Bildung, Wissenschaft und Kunst (Research Network ?Human Induced Pluripotent Stem cells? (For-IPS) and the European Commission (Health-FH-2010-242129, SyBoss) to WW, KNDD2 grant FKZ01GI1005D and Federal Ministry for Education and Research (BMBF) grant ?Funktionelle Tiermo-delle f?r die Kandidatengene der Alzheimerschen Erkrankung? (01GS08133) to TF and WW; NIH grants R01AG032383, K02AG041815, and R21NS090926, the Welch Foundation I-1660, and Texas Institute for Brain Injury and Repair to JH. We thank Dr Sakir Humayun Gultekin for advice in charac-terization of tumor pathology. Dr. Rongkun Shen and the OHSU Gene Profiling Resource performed and helped analyze the microarray results, Glen Corson helped with antibody generation and charac-terization, and Jennifer Miller, Andrea Ansari and Michaela Voorhees performed mouse husbandry, genotyping, and histology.
PY - 2016/1/8
Y1 - 2016/1/8
N2 - The timely transition from neural progenitor to post-mitotic neuron requires down-regulation and loss of the neuronal transcriptional repressor, REST. Here, we have used mice containing a gene trap in the Rest gene, eliminating transcription from all coding exons, to remove REST prematurely from neural progenitors. We find that catastrophic DNA damage occurs during S-phase of the cell cycle, with long-term consequences including abnormal chromosome separation, apoptosis, and smaller brains. Persistent effects are evident by latent appearance of proneural glioblastoma in adult mice deleted additionally for the tumor suppressor p53 protein (p53). A previous line of mice deleted for REST in progenitors by conventional gene targeting does not exhibit these phenotypes, likely due to a remaining C-terminal peptide that still binds chromatin and recruits co-repressors. Our results suggest that REST-mediated chromatin remodeling is required in neural progenitors for proper S-phase dynamics, as part of its well-established role in repressing neuronal genes until terminal differentiation.
AB - The timely transition from neural progenitor to post-mitotic neuron requires down-regulation and loss of the neuronal transcriptional repressor, REST. Here, we have used mice containing a gene trap in the Rest gene, eliminating transcription from all coding exons, to remove REST prematurely from neural progenitors. We find that catastrophic DNA damage occurs during S-phase of the cell cycle, with long-term consequences including abnormal chromosome separation, apoptosis, and smaller brains. Persistent effects are evident by latent appearance of proneural glioblastoma in adult mice deleted additionally for the tumor suppressor p53 protein (p53). A previous line of mice deleted for REST in progenitors by conventional gene targeting does not exhibit these phenotypes, likely due to a remaining C-terminal peptide that still binds chromatin and recruits co-repressors. Our results suggest that REST-mediated chromatin remodeling is required in neural progenitors for proper S-phase dynamics, as part of its well-established role in repressing neuronal genes until terminal differentiation.
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U2 - 10.7554/eLife.09584.001
DO - 10.7554/eLife.09584.001
M3 - Article
C2 - 26745185
AN - SCOPUS:84956908265
VL - 5
JO - eLife
JF - eLife
SN - 2050-084X
IS - JANUARY2016
M1 - e09584
ER -