YY1-dependent transcriptional regulation of the human GDAP1 gene

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Genomics. 2009 Aug 28.

YY1-dependent transcriptional regulation of the human GDAP1 gene.

Ratajewski M, Pulaski L.

Laboratory of Transcriptional Regulation, Institute of Medical Biology, Polish

Academy of Sciences, Lodz, Poland.

Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative condition,

some types of which (notably CMT4A) are caused by mutations in the GDAP1 gene

that encodes a protein of unknown molecular function implicated in regulation of

mitochondrial fission.

Here we present for the first time a functional analysis of the GDAP1 gene

promoter which we found to be transcriptionally regulated by YY1, a broadly

studied factor that seems to be involved in regulating many of the same cellular

phenomena as GDAP1. We show that GDAP1 is broadly expressed in cancer cell lines

of different tissue origin, contrasting with the restricted neuronal

distribution reported by some authors.

There is a consensus YY1 binding site in the GDAP1 core promoter which we show

to be functional in both in vitro binding assays and in living cells.

Overexpression of YY1 activated the GDAP1 promoter in a reporter gene system as

well as increased the level of endogenous mRNA. RNAi-mediated knockdown of YY1

in HEK293 cells led to decreased GDAP1 expression.

While YY1 is known to exert both positive and negative regulatory influences on

nuclear-encoded mitochondrial proteins, as well as on neurodegeneration-related

genes, in all cell lines we studied (including neuroblastoma) the effect of YY1

on GDAP1 expression is activatory. This leads to interesting conclusions about

the possible clinical role of this interaction and suggests a broader regulatory

network.