Demethylation of the coding region triggers the activation of the human testis-specific PDHA2 gene in somatic tissues.

Human PDHA2 is a testis-specific gene that codes for the E(1)α subunit of Pyruvate Dehydrogenase Complex (PDC), a crucial enzyme system in cell energy metabolism. Since activation of the PDHA2 gene in somatic cells could be a new therapeutic approach for PDC deficiency, we aimed to identify the regu...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Ana Pinheiro, Maria João Nunes, Inês Milagre, Elsa Rodrigues, Maria João Silva, Isabel Tavares de Almeida, Isabel Rivera
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/98f103d96456418c925534400a21098f
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:98f103d96456418c925534400a21098f
record_format	dspace
spelling	oai:doaj.org-article:98f103d96456418c925534400a21098f2021-11-18T07:16:34ZDemethylation of the coding region triggers the activation of the human testis-specific PDHA2 gene in somatic tissues.1932-620310.1371/journal.pone.0038076https://doaj.org/article/98f103d96456418c925534400a21098f2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22675509/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Human PDHA2 is a testis-specific gene that codes for the E(1)α subunit of Pyruvate Dehydrogenase Complex (PDC), a crucial enzyme system in cell energy metabolism. Since activation of the PDHA2 gene in somatic cells could be a new therapeutic approach for PDC deficiency, we aimed to identify the regulatory mechanisms underlying the human PDHA2 gene expression. Functional deletion studies revealed that the -122 to -6 promoter region is indispensable for basal expression of this TATA-less promoter, and suggested a role of an epigenetic program in the control of PDHA2 gene expression. Indeed, treatment of SH-SY5Y cells with the hypomethylating agent 5-Aza-2'-deoxycytidine (DAC) promoted the reactivation of the PDHA2 gene, by inducing the recruitment of the RNA polymerase II to the proximal promoter region and the consequent increase in PDHA2 mRNA levels. Bisulfite sequencing analysis revealed that DAC treatment induced a significant demethylation of the CpG island II (nucleotides +197 to +460) in PDHA2 coding region, while the promoter region remained highly methylated. Taken together with our previous results that show an in vivo correlation between PDHA2 expression and the demethylation of the CpG island II in testis germ cells, the present results show that internal methylation of the PDHA2 gene plays a part in its repression in somatic cells. In conclusion, our data support the novel finding that methylation of the PDHA2 coding region can inhibit gene transcription. This represents a key mechanism for absence of PDHA2 expression in somatic cells and a target for PDC therapy.Ana PinheiroMaria João NunesInês MilagreElsa RodriguesMaria João SilvaIsabel Tavares de AlmeidaIsabel RiveraPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 6, p e38076 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ana Pinheiro Maria João Nunes Inês Milagre Elsa Rodrigues Maria João Silva Isabel Tavares de Almeida Isabel Rivera Demethylation of the coding region triggers the activation of the human testis-specific PDHA2 gene in somatic tissues.
description	Human PDHA2 is a testis-specific gene that codes for the E(1)α subunit of Pyruvate Dehydrogenase Complex (PDC), a crucial enzyme system in cell energy metabolism. Since activation of the PDHA2 gene in somatic cells could be a new therapeutic approach for PDC deficiency, we aimed to identify the regulatory mechanisms underlying the human PDHA2 gene expression. Functional deletion studies revealed that the -122 to -6 promoter region is indispensable for basal expression of this TATA-less promoter, and suggested a role of an epigenetic program in the control of PDHA2 gene expression. Indeed, treatment of SH-SY5Y cells with the hypomethylating agent 5-Aza-2'-deoxycytidine (DAC) promoted the reactivation of the PDHA2 gene, by inducing the recruitment of the RNA polymerase II to the proximal promoter region and the consequent increase in PDHA2 mRNA levels. Bisulfite sequencing analysis revealed that DAC treatment induced a significant demethylation of the CpG island II (nucleotides +197 to +460) in PDHA2 coding region, while the promoter region remained highly methylated. Taken together with our previous results that show an in vivo correlation between PDHA2 expression and the demethylation of the CpG island II in testis germ cells, the present results show that internal methylation of the PDHA2 gene plays a part in its repression in somatic cells. In conclusion, our data support the novel finding that methylation of the PDHA2 coding region can inhibit gene transcription. This represents a key mechanism for absence of PDHA2 expression in somatic cells and a target for PDC therapy.
format	article
author	Ana Pinheiro Maria João Nunes Inês Milagre Elsa Rodrigues Maria João Silva Isabel Tavares de Almeida Isabel Rivera
author_facet	Ana Pinheiro Maria João Nunes Inês Milagre Elsa Rodrigues Maria João Silva Isabel Tavares de Almeida Isabel Rivera
author_sort	Ana Pinheiro
title	Demethylation of the coding region triggers the activation of the human testis-specific PDHA2 gene in somatic tissues.
title_short	Demethylation of the coding region triggers the activation of the human testis-specific PDHA2 gene in somatic tissues.
title_full	Demethylation of the coding region triggers the activation of the human testis-specific PDHA2 gene in somatic tissues.
title_fullStr	Demethylation of the coding region triggers the activation of the human testis-specific PDHA2 gene in somatic tissues.
title_full_unstemmed	Demethylation of the coding region triggers the activation of the human testis-specific PDHA2 gene in somatic tissues.
title_sort	demethylation of the coding region triggers the activation of the human testis-specific pdha2 gene in somatic tissues.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/98f103d96456418c925534400a21098f
work_keys_str_mv	AT anapinheiro demethylationofthecodingregiontriggerstheactivationofthehumantestisspecificpdha2geneinsomatictissues AT mariajoaonunes demethylationofthecodingregiontriggerstheactivationofthehumantestisspecificpdha2geneinsomatictissues AT inesmilagre demethylationofthecodingregiontriggerstheactivationofthehumantestisspecificpdha2geneinsomatictissues AT elsarodrigues demethylationofthecodingregiontriggerstheactivationofthehumantestisspecificpdha2geneinsomatictissues AT mariajoaosilva demethylationofthecodingregiontriggerstheactivationofthehumantestisspecificpdha2geneinsomatictissues AT isabeltavaresdealmeida demethylationofthecodingregiontriggerstheactivationofthehumantestisspecificpdha2geneinsomatictissues AT isabelrivera demethylationofthecodingregiontriggerstheactivationofthehumantestisspecificpdha2geneinsomatictissues
_version_	1718423680820707328

Demethylation of the coding region triggers the activation of the human testis-specific PDHA2 gene in somatic tissues.

Ejemplares similares