SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron

Abstract

A series of transcription factors critical for maintenance of the neural stem cell state have been identified, but the role of functionally important corepressors in maintenance of the neural stem cell state and early neurogenesis remains unclear. Previous studies have characterized the expression of both SMRT (also known as NCoR2, nuclear receptor co-repressor 2) and NCoR in a variety of developmental systems; however, the specific role of the SMRT corepressor in neurogenesis is still to be determined. Here we report a critical role for SMRT in forebrain development and in maintenance of the neural stem cell state. Analysis of a series of markers in SMRT-gene-deleted mice revealed the functional requirement of SMRT in the actions of both retinoic-acid-dependent and Notch-dependent forebrain development. In isolated cortical progenitor cells, SMRT was critical for preventing retinoic-acid-receptor-dependent induction of differentiation along a neuronal pathway in the absence of any ligand. Our data reveal that SMRT represses expression of the jumonji-domain containing gene JMJD3, a direct retinoic-acid-receptor target that functions as a histone H3 trimethyl K27 demethylase and which is capable of activating specific components of the neurogenic program.

Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide

“…To elucidate whether the effects of HDACi on H4K16 acetylation were cell specific or general in nature, we examined two additional cancer cell lines and a primary stem cell culture: NSCLC H1299 cell line, neuroblastoma SK-N-BE(2) cell line and primary fibroblast growth factor (FGF2)-expanded embryonic neural stem cells prepared from rat cortices (Jepsen et al, 2007;Andersson et al, 2009). SK-N-BE(2) is a highly malignant cell line derived from chemotherapy-resistant neuroblastoma, which presents an intrinsic resistance to multiple drugs including several DNA-damaging agents (Keshelava et al, 1998).…”

“…Isolation and culture of multipotent neural progenitors, referred to as neural stem cells, were performed essentially as described elsewhere (Jepsen et al, 2007;Andersson et al, 2009). In brief, cortices from rats at embryonic day 15 were dissected and mechanically dispersed in a modified serum-free, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)-free N2-supplemented Dulbecco's modified Eagle's medium/ F12 medium.…”

Epigenetic regulation of aging stem cells

“…Consistently, overexpression of JMJD3 drives premature keratinocyte differentiation (Sen et al, 2008). Similarly, in the developing nervous system of mice, JMJD3 promotes differentiation upon induction of retinoic acid signaling, and its suppression is required for the maintenance of an uncommitted stem cell state (Jepsen et al, 2007). The role for JMJD3 in adult NSCs has not yet been determined, but altered JMJD3 activity in aging NSC populations may promote loss of a stem cell state by inappropriate initiation of differentiation programs or by de-repression of the p16 Ink4a /p19 Arf locus, as has been reported in fibroblasts (Agger et al, 2009;Barradas et al, 2009).…”

p57Kip2 is a repressor of Mash1 activity and neuronal differentiation in neural stem cells

“…The telencephalic NSCs can rapidly and efficiently be differentiated into neurons, astrocytes, and smooth muscle-like cells after various treatments as assessed by morphology and cell fate markers. 6,7,25,26 For example, treatment of NSCs with PDGF, BDNF, or valproic acid results in increased neuronal differentiation and TuJ1 antibody staining, CNTF, LIF, CT1, or BMP4 treatment induce astrocytic differentiation and increased GFAP staining, and treatment with fetal bovine serum or BMP4 yields increased mesenchymal differentiation and increased numbers of cells expressing smooth muscle actin (SMA) (Supplementary Figure 1F-H).…”

“…3,4 Transcriptional repression of astrocytic genes and thus the correct numbers of progenitors and neurons at these late events, instead depends on other factors such as the Notch-regulated transcription factor CSL/RBP-Jk and the co-repressors N-CoR and SMRT. 6,7 In addition, neurogenic members of the basic helix-loop-helix (bHLH) family of transcription factors, such as Mash1 and Neurogenin (Ngn) 2, interferes with astrocyte differentiation in multipotent neural progenitors at least in part by sequestering the coactivators CBP/p300 required for astrocyte differentiation. 8 Less is understood regarding a corresponding repression of neuronal differentiation during glial differentiation.…”