Chromatin Remodeling Factor Brg1 Supports the Early Maintenance and Late Responsiveness of Nestin-Lineage Adult Neural Stem and Progenitor Cells

Abstract

Insights from embryonic development suggest chromatin remodeling is important in adult neural stem cells (aNSCs) maintenance and self-renewal, but this concept has not been fully explored in the adult brain. To assess the role of chromatin remodeling in adult neurogenesis, we inducibly deleted Brg1 – the core subunit of SWI/SNF-like BAF chromatin remodeling complexes – in nestin-expressing aNSCs and their progeny in vivo and in culture. This resulted in abnormal adult neurogenesis in the hippocampus, which initially reduced hippocampal aNSCs and progenitor maintenance, and later reduced its responsiveness to physiological stimulation. Mechanistically, deletion of Brg1 appeared to impair cell cycle progression, which is partially due to elevated p53 pathway and p21 expression. Knockdown of p53 rescued the neurosphere growth defects caused by Brg1 deletion. Our results show that epigenetic chromatin remodeling (via a Brg1 and p53/p21-dependent process) determines the aNSCs and progenitor maintenance and responsiveness of neurogenesis.

Chromatin-remodelling factor Brg1 regulates myocardial proliferation and regeneration in zebrafish

“…Our data support the notion that an increase of CDK inhibitors and related meis genes occurs after inhibition of Brg1 during heart regeneration in zebrafish; this was partly supported by RNA-seq analysis of Tg( hsp70 :dn-xBrg1) and wild-type sibling hearts after daily heat shock from 5 to 14 d.p.a., as well as being further confirmed by quantitative RT–PCR and its myocardial enrichment by RNAscope in situ hybridization analysis. During regeneration, cdkn1c was downregulated in injured hearts at 3 and 5 d.p.a., while brg1 was reciprocally upregulated, suggesting that Brg1 normally represses cdkn1c expression during this process, consistent with previous reports that cell-cycle-dependent kinase inhibitors are downstream of Brg1 in cardiac development17, mammalian neural crest cell development24, bulge stem cells during tissue regeneration26 and adult neural stem cells maintenance46, as well as Brg1 directly binds to the cdkn1c promoter as predicted by ChIP-seq analysis47. Furthermore, our data showed that Brg1 directly bound to the promoter of cdkn1c by ChIP assay, repressed the cdkn1c -luciferase reporter, and siRNA knockdown of either cdkn1a or cdkn1c partially rescued the blunted myocardial proliferation with transgenic over-expression of dn- xBrg1 .…”

Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders

“…The study showed that by directly interacting with Pax6, the BRG1-ATPase core of BAF complex is able to potentiate the recruitment of neurogenic transcription factors such as Sox11, Nfib, and Pou3f4 to Pax6 gene targets, thereby forming regulatory feedback network in orchestrating fate specification during adult neurogenesis. Adult NSCs lose neuronal fate tendency and become bias toward glial cell lineage upon deletion of BRG1 just as in the case of Pax6 ablation (Ninkovic et al, 2013 ; Petrik et al, 2015 ).…”

Control of adult neurogenesis by programmed cell death in the mammalian brain

“…Retroviral injection is useful for the direct visualization of newborn neurons, but it requires invasive surgical procedures and covers only a limited number of new neurons [ 17 – 21 ]. Non-invasive genetic labeling of adult-born cells in transgenic animal models, such as the inducible Cre recombinase and tamoxifen-regulated system (Cre-ER), is an alternative approach that is now being successfully applied [ 22 – 25 ]. Specific markers for NSCs and newborn neurons cover the entire population of newborn cells and can be used for human samples, but they are expressed transiently and sometimes nonspecifically in other cell types.…”