Specificity Protein 1 (Sp1)-dependent Activation of the Synapsin I Gene (SYN1) Is Modulated by RE1-silencing Transcription Factor (REST) and 5′-Cytosine-Phosphoguanine (CpG) Methylation

Paonessa, Francesco; Latifi, Shahrzad; Scarongella, Helena; Cesca, Fabrizia; Benfenati, Fabio

doi:10.1074/jbc.m112.399782

Cited by 49 publications

(38 citation statements)

References 56 publications

(61 reference statements)

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“…We previously found that differentiation of N2a cells induced by retinoic acid (RA) treatment is associated with loss of endogenous REST activity and increased expression of its target genes (28). Indeed, we found that neurite outgrowth was enhanced in differentiating N2a cells transfected with the open form of the AsLOV2-PAH1b with respect to the cells expressing the closed form of the chimera (Fig.…”

Section: Resultsmentioning

confidence: 84%

“…2F). Similarly, when the AsLOV2-PAH1b constructs were expressed in N2a cells, the transcription of the endogenous SYN1, NAV1.2, and BDNF genes, which are well-known REST targets (9,28), was significantly up-regulated only in cells containing the open chimera (Fig. 2G).…”

Section: Resultsmentioning

confidence: 86%

“…The analysis was performed using the nSolver Analysis Software 2.5. Primer sequences and numerical values are reported in Tables S1 and S2. expression of the neuron-specific SYN1 gene, a well-known REST target (28), in Neuro2a (N2a) neuroblastoma cells. Indeed, a comparable increase in SYN1 gene transcription was apparent when cells were transfected with either mSin3a-N205 or RILP-N313 or silenced for REST with shRNAs (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Regulation of neural gene transcription by optogenetic inhibition of the RE1-silencing transcription factor

Paonessa

Criscuolo

Sacchetti

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Optogenetics provides new ways to activate gene transcription; however, no attempts have been made as yet to modulate mammalian transcription factors. We report the light-mediated regulation of the repressor element 1 (RE1)-silencing transcription factor (REST), a master regulator of neural genes. To tune REST activity, we selected two protein domains that impair REST-DNA binding or recruitment of the cofactor mSin3a. Computational modeling guided the fusion of the inhibitory domains to the light-sensitive Avena sativa lightoxygen-voltage-sensing (LOV) 2-phototrophin 1 (AsLOV2). By expressing AsLOV2 chimeras in Neuro2a cells, we achieved light-dependent modulation of REST target genes that was associated with an improved neural differentiation. In primary neurons, light-mediated REST inhibition increased Na + -channel 1.2 and brain-derived neurotrophic factor transcription and boosted Na + currents and neuronal firing. This optogenetic approach allows the coordinated expression of a cluster of genes impinging on neuronal activity, providing a tool for studying neuronal physiology and correcting gene expression changes taking place in brain diseases.

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Section: Resultsmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

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Regulation of neural gene transcription by optogenetic inhibition of the RE1-silencing transcription factor

Paonessa

Criscuolo

Sacchetti

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Finally, we confirmed that CREB and Nurr1 are active enhancers of SYN1 and SYN2 promoter activities. Other transcription factors have been recently identified to positively regulate SYN1 promoter activity, including Sp1 at sites immediately distal and proximal from the proximal CREB site (64), which raises the possibility that Sp1 and CREB might cooperate to control SYN1 expression.…”

Section: Dependence On Endogenous αSyn For Exogenous O-αsyn To Inducementioning

confidence: 99%

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Larson

Greimel

Amar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (αSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric αSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of αSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human αSyn in an AD mouse model, we artificially enhanced αSyn oligomerization. These bigenic mice displayed exacerbated Aβ-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble αSyn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric αSyn but not monomeric αSyn was causing a lowering in synapsin-I/II protein abundance. For a particular αSyn oligomer, these changes were either dependent or independent on endogenous αSyn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by αSyn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous αSyn oligomers can impair memory by selectively lowering synapsin expression.α-synuclein | oligomer | memory | Alzheimer's disease | synapsins

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“…Cytosine methylation-mediated interference of Sp1 binding to its cis-elements on promoters is known to inhibit the expression of several of its target genes in various tissues (2,7,17). We (23) have previously demonstrated that Sp1 activates basal ␣ENaC transcription in mIMCD3 cells and that aldosterone enhances Sp1 binding to, and trans-activation of, the ␣ENaC promoter, without altering nuclear Sp1 protein levels.…”

Section: Dnmt3b and Mbd4 Contribute To The Basal Repression Of ␣Enac mentioning

confidence: 98%

Aldosterone reprograms promoter methylation to regulate αENaC transcription in the collecting cuct

Kong

Kone

2013

American Journal of Physiology-Renal Physiology

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Yu Z, Kong Q, Kone BC. Aldosterone reprograms promoter methylation to regulate ␣ENaC transcription in the collecting cuct. Am J Physiol Renal Physiol 305: F1006 -F1013, 2013. First published August 7, 2013 doi:10.1152/ajprenal.00407.2013.-Aldosterone increases tubular Na ϩ absorption largely by increasing ␣-epithelial Na ϩ channel (␣ENaC) transcription in collecting duct principal cells. How aldosterone reprograms basal ␣ENaC transcription to high-level activity in the collecting duct is incompletely understood. Promoter methylation, a covalent but reversible epigenetic process, has been implicated in the control of gene expression in health and disease. We investigated the role of promoter methylation/demethylation in the epigenetic control of basal and aldosterone-stimulated ␣ENaC transcription in mIMCD3 collecting duct cells. Bisulfite treatment and sequencing analysis after treatment of the cells with the DNA methyltransferase (DNMT) inhibitor 5-aza-2=-deoxycytidine (5-Aza-CdR) identified clusters of methylated cytosines in a CpG island near the transcription start site of the ␣ENaC promoter. 5-Aza-CdR treatment or small interfering RNA-mediated knockdown of DNMT3b or methyl-CpG-binding domain protein (MBD)-4 derepressed basal ␣ENaC transcription, indicating that promoter methylation suppresses basal ␣ENaC transcription. Aldosterone triggered a time-dependent decrease in 5mC and DNMT3b and a concurrent enrichment in 5-hydroxymethylcytosine (5hmC) and ten-eleven translocation (Tet)2 at the ␣ENaC promoter, consistent with active demethylation. 5-AzaCdR mimicked aldosterone by enhancing Sp1 binding to the ␣ENaC promoter. We conclude that DNMT3b-and MBD4-dependent methylation of the ␣ENaC promoter limits basal ␣ENaC transcription, in part by limiting Sp1 binding and trans-activation. Aldosterone stimulates the dispersal of DNMT3b and recruitment of Tet2 to demethylate the ␣ENaC promoter to induce ␣ENaC transcription. These results disclose a novel epigenetic mechanism for the control of basal and aldosterone-induced ␣ENaC transcription that adds to previously described epigenetic controls exerted by histone modifications. epigenetic; chromatin; transcription factor; methylcytosine; methyltransferase; epithelial Na ϩ channel THE EPITHELIAL NA ϩ CHANNEL (ENaC) mediates Na ϩ entry across the apical membranes of salt-absorbing epithelia of the kidney, distal colon, and lung and functions as the rate-limiting step in active transepithelial Na ϩ and fluid absorption. In serving this role, ENaC plays important roles in the regulation of extracellular fluid volume and blood pressure (1,20). Of the three ENaC subunits (␣, ␤, and ␥), ␣ENaC appears to be critical to the overall salt balance, as evidenced by the finding that mice with targeted inactivation of ␣ENaC in the connecting tubule (CNT)/collecting duct (CD) exhibit severe renal salt wasting characteristic of a pseudohypoaldosteronism type I phenotype (5). ␣ENaC is also a molecular target of aldosterone, which stimulates its transcription in a manner that is rate l...

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Specificity Protein 1 (Sp1)-dependent Activation of the Synapsin I Gene (SYN1) Is Modulated by RE1-silencing Transcription Factor (REST) and 5′-Cytosine-Phosphoguanine (CpG) Methylation

Cited by 49 publications

References 56 publications

Regulation of neural gene transcription by optogenetic inhibition of the RE1-silencing transcription factor

Regulation of neural gene transcription by optogenetic inhibition of the RE1-silencing transcription factor

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Aldosterone reprograms promoter methylation to regulate αENaC transcription in the collecting cuct

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