Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation

Abstract

20Adult neural stem cells are largely quiescent, and require transcriptional reprogramming 21 to reenter the cell cycle and undergo neurogenesis. However, the precise mechanisms 22 that underlie the rapid transcriptional overhaul during NSC activation remain undefined. 23Here, we identify the genome-wide chromatin accessibility differences between primary 24 neural stem and progenitor cells in quiescent and activated states. We show that these 25 distinct cellular states exhibit both shared and unique chromatin profiles, which are both 26 associated with gene regulation. Interestingly, we find that accessible chromatin states 27 specific to quiescent or activated cells are active enhancers bound by pro-neurogenic 28 and quiescence factors, ASCL1 and NFI. In contrast, shared sites are gene promoters 29 harboring constitutively accessible chromatin enriched for particular core promoter 30 elements that are functionally associated with translation and metabolic functions. 31Together, our findings reveal how accessible chromatin states regulate a transcriptional 32 overhaul and drive the switch between quiescence and proliferation in NSC activation. 33 34 46In vivo, the majority of NSCs reside in a state of quiescence 10 . Quiescent NSCs (qNSCs) 47 have exited the cell cycle but can be prompted by intrinsic or extrinsic cues to "activate" 48 and re-enter the cell cycle (we refer to these cells as activated NSCs, or aNSCs). Once 49 activated, aNSCs proliferate and may return to quiescence and self-renew, or 50 differentiate into neurons or glia. Activation of qNSCs is the first critical step in 51 neurogenesis in the adult brain, and is enhanced in response to damage (e.g. stroke) or 52 environmental stimuli such as parabiosis [11][12][13] . Evidence shows that decreased 53 neurogenesis with age occurs due to reduced activation of qNSCs, senescence of the 54 NSC niche, and exhaustion of the qNSC pool [14][15][16][17] . Accumulation of qNSCs has also been 55 observed in a rodent model for neurodevelopmental disorders, suggesting that a careful 56 balance of NSC quiescence and activation is necessary for healthy cognitive function 18 . 57However, the precise mechanisms that regulate this balance and prompt qNSCs to re-58 enter the cell cycle in the healthy mammalian brain are mostly unknown. 59 60 Recent studies reported that quiescent and activated NSCs employ cell type-specific 61 mechanisms to support their functionality, including distinct metabolic states and 62 differences in proteostasis [19][20][21] . Transcriptional profiling of qNSCs and aNSCs revealed 63 both shared and distinct transcriptional signatures in the two cell types, indicating that a 64 transcriptional overhaul occurs at a subset of genes during the process of NSC 65 activation 10,19,22,23 . For example, genes involved in cell proliferation, lipid metabolism, and 66 protein homeostasis were differentially expressed in quiescent and activated NSCs. 67 Similar changes have also been observed using in vitro models of NSC quiescence and 68 activation...

An epigenome atlas of neural progenitors within the embryonic mouse forebrain

“…One exception are the four cortical AP clusters, which had greater similarity between each other compared to other clusters. The cell type- and brain region-specific DA peak profiles are consistent with previous models of chromatin reorganization during cellular differentiation (Hu et al, 2018; Maybury-Lewis et al, 2020; Preissl et al, 2018).…”

“…Nearly half of all such Cicero connections were enriched in AP nuclei, which is consistent with an overall decrease in accessibility as development progresses (Figures S3B-C) and indicates a progressive change in the Cicero connection profiles as development proceeds. As chromatin regions with dynamic accessibility are associated with gene regulation during neural stem cell activation (Maybury-Lewis et al, 2020), we hypothesized that the Cicero connections which became more prevelant in immature neurons might encode lineage specific cREs that may play a role in neuronal lineage commitment.…”

The eroding chromatin landscape of aging stem cells

“…However, in injury-activated old MuSCs, H3K4me3 is upregulated at several cell cycle inhibitor genes such as p21 and p16, which partly explains the decline in the proliferative capacity of these cells [ 77 ]. In genome-wide studies using NSC populations from postnatal day 5 mice, H3K4me3 was also a stable mark at promoters of genes that are differentially expressed with NSC activation, consistent with its enrichment at constitutively accessible chromatin rather than correlating with the change in transcription [ 78 ]. Furthermore, as in HSCs, broad H3K4me3 domains promote the self-renewal and differentiation of mouse NSCs [ 79 ].…”