De-regulated expression of the BRG1 chromatin remodeling factor in bone marrow mesenchymal stromal cells induces senescence associated with the silencing of NANOG and changes in the levels of chromatin proteins

Cell Cycle
T SquillaroUmberto Galderisi

Abstract

Stem cells have a peculiar chromatin architecture that contributes to their unique properties, including uncommitted status, multi/pluripotency and self-renewal. We analyzed the effect of the de-regulation of the SWI/SNF chromatin remodeling complex in mesenchymal stromal cells (MSC) through the silencing and up-regulation of BRG1, which is the ATPase subunit of the complex. The altered expression of BRG1 promoted the senescence of MSC with suppression of the NANOG transcription, which is part of the transcriptional circuitry governing stem cell functions. To gain insight on the way NANOG was silenced, we evaluated how the de-regulated BRG1 expression affect the binding of activators and repressors on the NANOG promoter. We found 4 E2F binding motifs on NANOG promoter, which can be occupied by RB1 and RB2/P130. These are members of the retinoblastoma gene family. In MSC with a silenced BRG1, the relative binding of the 2 retinoblastoma proteins increased, and this was associated with the recruitment of DNMT1. This induced the methylation of CpG on the NANOG promoter. Opposingly, when a high level of BRG1 was present, the same E2F binding motifs were docking sites for BRG1, which induced chromatin compaction without CpG methylat...Continue Reading

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Citations

Mar 18, 2016·The Physician and Sportsmedicine·Masters M RichardsJafar Golzarian
Sep 10, 2017·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Li-Qin ChengDe-Pei Liu
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Feb 27, 2020·Biomolecules·Simona Neri, Rosa Maria Borzì
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Nov 19, 2020·Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology·Musashi Kubiura-IchimaruMasako Tada

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Datasets Mentioned

BETA
GI
224589803

Methods Mentioned

BETA
immunoprecipitation
PCR
histone acetylation
acetylation
CHART
CHART-PCR
electrophoresis
scraping

Software Mentioned

Methprimer
Primer Express
PATCH
JASPAR
EasyProt
Rad
Bio
Proscan
TIBCO Spotfire
DAVID

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