The Transcriptional Complex Sp1/KMT2A by Up-Regulating Restrictive Element 1 Silencing Transcription Factor Accelerates Methylmercury-Induced Cell Death in Motor Neuron-Like NSC34 Cells Overexpressing SOD1-G93A

Methylmercury (MeHg) exposure has been related to amyotrophic lateral sclerosis (ALS) pathogenesis and molecular mechanisms of its neurotoxicity has been associated to an overexpression of the Restrictive Element 1 Silencing Transcription factor (REST). Herein, we evaluated the possibility that MeHg...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Natascia Guida, Luca Sanguigno, Luigi Mascolo, Lucrezia Calabrese, Angelo Serani, Pasquale Molinaro, C. Geoffrey Lau, Lucio Annunziato, Luigi Formisano
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	MeHg SOD1-G93A Sp transcription factors REST (RE-1 silencing transcription factor) motor neuronal cell death Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/89a302f1e8e84e34bd6a9666029f77d1
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:89a302f1e8e84e34bd6a9666029f77d1
record_format	dspace
spelling	oai:doaj.org-article:89a302f1e8e84e34bd6a9666029f77d12021-12-01T08:21:16ZThe Transcriptional Complex Sp1/KMT2A by Up-Regulating Restrictive Element 1 Silencing Transcription Factor Accelerates Methylmercury-Induced Cell Death in Motor Neuron-Like NSC34 Cells Overexpressing SOD1-G93A1662-453X10.3389/fnins.2021.771580https://doaj.org/article/89a302f1e8e84e34bd6a9666029f77d12021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnins.2021.771580/fullhttps://doaj.org/toc/1662-453XMethylmercury (MeHg) exposure has been related to amyotrophic lateral sclerosis (ALS) pathogenesis and molecular mechanisms of its neurotoxicity has been associated to an overexpression of the Restrictive Element 1 Silencing Transcription factor (REST). Herein, we evaluated the possibility that MeHg could accelerate neuronal death of the motor neuron-like NSC34 cells transiently overexpressing the human Cu2+/Zn2+superoxide dismutase 1 (SOD1) gene mutated at glycine 93 (SOD1-G93A). Indeed, SOD1-G93A cells exposed to 100 nM MeHg for 24 h showed a reduction in cell viability, as compared to cells transfected with empty vector or with unmutated SOD1 construct. Interestingly, cell survival reduction in SOD1-G93A cells was associated with an increase of REST mRNA and protein levels. Furthermore, MeHg increased the expression of the transcriptional factor Sp1 and promoted its binding to REST gene promoter sequence. Notably, Sp1 knockdown reverted MeHg-induced REST increase. Co-immunoprecipitation experiments demonstrated that Sp1 physically interacted with the epigenetic writer Lysine-Methyltransferase-2A (KMT2A). Moreover, knocking-down of KMT2A reduced MeHg-induced REST mRNA and protein increase in SOD1-G93A cells. Finally, we found that MeHg-induced REST up-regulation triggered necropoptotic cell death, monitored by RIPK1 increased protein expression. Interestingly, REST knockdown or treatment with the necroptosis inhibitor Necrostatin-1 (Nec) decelerated MeH-induced cell death in SOD1-G93A cells. Collectively, this study demonstrated that MeHg hastens necroptotic cell death in SOD1-G93A cells via Sp1/KMT2A complex, that by epigenetic mechanisms increases REST gene expression.Natascia GuidaLuca SanguignoLuigi MascoloLucrezia CalabreseAngelo SeraniPasquale MolinaroC. Geoffrey LauLucio AnnunziatoLuigi FormisanoFrontiers Media S.A.articleMeHgSOD1-G93ASp transcription factorsREST (RE-1 silencing transcription factor)motor neuronal cell deathNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Neuroscience, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	MeHg SOD1-G93A Sp transcription factors REST (RE-1 silencing transcription factor) motor neuronal cell death Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	MeHg SOD1-G93A Sp transcription factors REST (RE-1 silencing transcription factor) motor neuronal cell death Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Natascia Guida Luca Sanguigno Luigi Mascolo Lucrezia Calabrese Angelo Serani Pasquale Molinaro C. Geoffrey Lau Lucio Annunziato Luigi Formisano The Transcriptional Complex Sp1/KMT2A by Up-Regulating Restrictive Element 1 Silencing Transcription Factor Accelerates Methylmercury-Induced Cell Death in Motor Neuron-Like NSC34 Cells Overexpressing SOD1-G93A
description	Methylmercury (MeHg) exposure has been related to amyotrophic lateral sclerosis (ALS) pathogenesis and molecular mechanisms of its neurotoxicity has been associated to an overexpression of the Restrictive Element 1 Silencing Transcription factor (REST). Herein, we evaluated the possibility that MeHg could accelerate neuronal death of the motor neuron-like NSC34 cells transiently overexpressing the human Cu2+/Zn2+superoxide dismutase 1 (SOD1) gene mutated at glycine 93 (SOD1-G93A). Indeed, SOD1-G93A cells exposed to 100 nM MeHg for 24 h showed a reduction in cell viability, as compared to cells transfected with empty vector or with unmutated SOD1 construct. Interestingly, cell survival reduction in SOD1-G93A cells was associated with an increase of REST mRNA and protein levels. Furthermore, MeHg increased the expression of the transcriptional factor Sp1 and promoted its binding to REST gene promoter sequence. Notably, Sp1 knockdown reverted MeHg-induced REST increase. Co-immunoprecipitation experiments demonstrated that Sp1 physically interacted with the epigenetic writer Lysine-Methyltransferase-2A (KMT2A). Moreover, knocking-down of KMT2A reduced MeHg-induced REST mRNA and protein increase in SOD1-G93A cells. Finally, we found that MeHg-induced REST up-regulation triggered necropoptotic cell death, monitored by RIPK1 increased protein expression. Interestingly, REST knockdown or treatment with the necroptosis inhibitor Necrostatin-1 (Nec) decelerated MeH-induced cell death in SOD1-G93A cells. Collectively, this study demonstrated that MeHg hastens necroptotic cell death in SOD1-G93A cells via Sp1/KMT2A complex, that by epigenetic mechanisms increases REST gene expression.
format	article
author	Natascia Guida Luca Sanguigno Luigi Mascolo Lucrezia Calabrese Angelo Serani Pasquale Molinaro C. Geoffrey Lau Lucio Annunziato Luigi Formisano
author_facet	Natascia Guida Luca Sanguigno Luigi Mascolo Lucrezia Calabrese Angelo Serani Pasquale Molinaro C. Geoffrey Lau Lucio Annunziato Luigi Formisano
author_sort	Natascia Guida
title	The Transcriptional Complex Sp1/KMT2A by Up-Regulating Restrictive Element 1 Silencing Transcription Factor Accelerates Methylmercury-Induced Cell Death in Motor Neuron-Like NSC34 Cells Overexpressing SOD1-G93A
title_short	The Transcriptional Complex Sp1/KMT2A by Up-Regulating Restrictive Element 1 Silencing Transcription Factor Accelerates Methylmercury-Induced Cell Death in Motor Neuron-Like NSC34 Cells Overexpressing SOD1-G93A
title_full	The Transcriptional Complex Sp1/KMT2A by Up-Regulating Restrictive Element 1 Silencing Transcription Factor Accelerates Methylmercury-Induced Cell Death in Motor Neuron-Like NSC34 Cells Overexpressing SOD1-G93A
title_fullStr	The Transcriptional Complex Sp1/KMT2A by Up-Regulating Restrictive Element 1 Silencing Transcription Factor Accelerates Methylmercury-Induced Cell Death in Motor Neuron-Like NSC34 Cells Overexpressing SOD1-G93A
title_full_unstemmed	The Transcriptional Complex Sp1/KMT2A by Up-Regulating Restrictive Element 1 Silencing Transcription Factor Accelerates Methylmercury-Induced Cell Death in Motor Neuron-Like NSC34 Cells Overexpressing SOD1-G93A
title_sort	transcriptional complex sp1/kmt2a by up-regulating restrictive element 1 silencing transcription factor accelerates methylmercury-induced cell death in motor neuron-like nsc34 cells overexpressing sod1-g93a
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/89a302f1e8e84e34bd6a9666029f77d1
work_keys_str_mv	AT natasciaguida thetranscriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT lucasanguigno thetranscriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT luigimascolo thetranscriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT lucreziacalabrese thetranscriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT angeloserani thetranscriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT pasqualemolinaro thetranscriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT cgeoffreylau thetranscriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT lucioannunziato thetranscriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT luigiformisano thetranscriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT natasciaguida transcriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT lucasanguigno transcriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT luigimascolo transcriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT lucreziacalabrese transcriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT angeloserani transcriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT pasqualemolinaro transcriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT cgeoffreylau transcriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT lucioannunziato transcriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a AT luigiformisano transcriptionalcomplexsp1kmt2abyupregulatingrestrictiveelement1silencingtranscriptionfactoracceleratesmethylmercuryinducedcelldeathinmotorneuronlikensc34cellsoverexpressingsod1g93a
_version_	1718405365373075456

The Transcriptional Complex Sp1/KMT2A by Up-Regulating Restrictive Element 1 Silencing Transcription Factor Accelerates Methylmercury-Induced Cell Death in Motor Neuron-Like NSC34 Cells Overexpressing SOD1-G93A

Ejemplares similares