Epigenetic regulation of the human GDAP1 gene

TL;DR

This paper shows that the GDAP1 gene, linked to a neurodegenerative disease and cancer survival, is regulated by epigenetic mechanisms like DNA methylation and histone acetylation.

Contribution

The study identifies for the first time that GDAP1 expression is epigenetically regulated via methylation of its promoter CpG island.

Findings

Methylation of the GDAP1 promoter CpG island inhibits gene activity.

Methyltransferase and HDAC inhibitors increase GDAP1 expression by altering epigenetic marks.

GDAP1 regulation occurs through sequences in the basal promoter region.

Abstract

Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene are linked to Charcot–Marie–Tooth (CMT) disease, a hereditary neurodegenerative condition. The protein encoded by this gene is involved in mitochondrial fission and calcium homeostasis. Recently, GDAP1 has also been implicated in the survival of patients with certain cancers. Despite its significant role in specific cellular processes and associated diseases, the mechanisms regulating GDAP1 expression are largely unknown. Here, we show for the first time that methylation of the CpG island in the proximal promoter of the GDAP1 gene inhibits its activity. Treating cells with low GDAP1 expression using methyltransferase and HDAC inhibitors induced the expression of this gene and its encoded protein. This induction was associated with promoter demethylation and increased association of acetylated histones with the GDAP1 promoter. Thus, we identified a mechanism that could be used to manipulate GDAP1 expression.

•A CpG island was identified in the proximal GDAP1 promoter.•In vitro methylation inhibits GDAP1 promoter activity.•A DNA methyltransferase inhibitor induces GDAP1 expression and decreases methylation of the identified CpG island.•An HDAC inhibitor increases GDAP1 expression and enhances the association of acetylated histones with the gene promoter.•Human GDAP1 is epigenetically regulated through sequences located in the basal promoter.

A CpG island was identified in the proximal GDAP1 promoter.

In vitro methylation inhibits GDAP1 promoter activity.

A DNA methyltransferase inhibitor induces GDAP1 expression and decreases methylation of the identified CpG island.

An HDAC inhibitor increases GDAP1 expression and enhances the association of acetylated histones with the gene promoter.

Human GDAP1 is epigenetically regulated through sequences located in the basal promoter.

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