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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.

Demethylation of the Coding Region Triggers the Activation of the Human Testis-Specific PDHA2 Gene in Somatic Tissues