Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation

Abstract

Neural precursor cells (NPCs) differentiate into neurons, astrocytes, and oligodendrocytes in response to intrinsic and extrinsic changes. Notch signals maintain undifferentiated NPCs, but the mechanisms underlying the neuronal differentiation are largely unknown. We show that SIRT1, an NAD ؉ -dependent histone deacetylase, modulates neuronal differentiation. SIRT1 was found in the cytoplasm of embryonic and adult NPCs and was transiently localized in the nucleus in response to differentiation stimulus. SIRT1 started to translocate into the nucleus within 10 min after the transfer of NPCs into differentiation conditions, stayed in the nucleus, and then gradually retranslocated to the cytoplasm after several hours. The number of neurospheres that generated Tuj1 ؉ neurons was significantly decreased by pharmacological inhibitors of SIRT1, dominant-negative SIRT1 and SIRT1-siRNA, whereas overexpression of SIRT1, but not that of cytoplasm-localized mutant SIRT1, enhanced neuronal differentiation and decreased Hes1 expression. Expression of SIRT1-siRNA impaired neuronal differentiation and migration of NPCs into the cortical plate in the embryonic brain. Nuclear receptor corepressor (N-CoR), which has been reported to bind SIRT1, promoted neuronal differentiation and synergistically increased the number of Tuj1 ؉ neurons with SIRT1, and both bound the Hes1 promoter region in differentiating NPCs. Hes1 transactivation by Notch1 was inhibited by SIRT1 and/or N-CoR. Our study indicated that SIRT1 is a player of repressing Notch1-Hes1 signaling pathway, and its transient translocation into the nucleus may have a role in the differentiation of NPCs.

Hypoxia Increases Sirtuin 1 Expression in a Hypoxia-inducible Factor-dependent Manner

“…Studies of Sirt1 activation to date have primarily focused on post-translational mechanisms of regulation. These mechanisms include changes in pyridine nucleotide levels or ratios that affect Sirt1 enzymatic activity, Sirt1 phosphorylation or other kinase-induced effects (35)(36)(37)(38)(39)(40), or Sirt1 subcellular localization (41)(42)(43)(44). Changes in pyridine nucleotide levels or ratios are perhaps the best studied mechanism for regulating Sirt1 function (45).…”

Resveratrol Improves Cardiomyopathy in Dystrophin-deficient Mice through SIRT1 Protein-mediated Modulation of p300 Protein*

“…Recently, SIRT1 was found to be an attractive therapeutic target for various diseases (7), and a polyphenol resveratrol was identified as a SIRT1 activator (8), although the mechanism of SIRT1 activation by resveratrol seems to be mediated by other molecules such as AMP-dependent protein kinase (7, 9 -11). We have shown that SIRT1 is a nucleocytoplasmic shuttling protein (12,13). Furthermore, we found that resveratrol increases superoxide dismutase 2, inhibits cardiomyocyte death, and prolongs the life span in TO-2 cardiomyopathic hamsters (14).…”

Epigenetic regulation of aging stem cells

“…Defects in HSC self-renewal under both basal and low oxygen conditions are exacerbated in older mice compared with young adults (Ou et al, 2010). The role of SIRT1 in adult NSCs has not yet been characterized, but SIRT1 plays a role in directing cell fate decisions of embryonic neural progenitors in response to different extracellular conditions (Hisahara et al, 2008;Prozorovski et al, 2008). In the presence of low amounts of growth factors, SIRT1 promotes neuronal differentiation in cultures of murine neural progenitors, and acute deletion of Sirt1 at embryonic stages results in fewer neurons in vivo (Hisahara et al, 2008).…”

“…The role of SIRT1 in adult NSCs has not yet been characterized, but SIRT1 plays a role in directing cell fate decisions of embryonic neural progenitors in response to different extracellular conditions (Hisahara et al, 2008;Prozorovski et al, 2008). In the presence of low amounts of growth factors, SIRT1 promotes neuronal differentiation in cultures of murine neural progenitors, and acute deletion of Sirt1 at embryonic stages results in fewer neurons in vivo (Hisahara et al, 2008). However, under conditions of mild oxidative stress, SIRT1 contributes to decreased production of neurons and increased astrocytes, an effect linked to SIRT1's effects on H3K9ac levels of proneural gene Mash1/Ascl1 (Prozorovski et al, 2008).…”