Mitochondrial maintenance & PGC-1alpha
Commentary
Cell Science Reviews Vol 6 No 2
ISSN 1742-8130
One more trick in the regulation of PGC-1α
Zhen Yan
Department of Medicine-Cardiovascular Medicine, Center for Skeletal Muscle Research at Robert M. Berne
Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
Received 24th October © Cell Science 2009
PGC-1α is a transcription coactivator centrally involved in the regulation of
energy balance and metabolism. A recent study in Cell Metabolism adds
another role for Pgc-1α, namely gene regulation in mitochondrial maintenance
and metabolic homeostasis. The latest findings indicate significant increases in
levels of DNA methylation within the promoter region of the Pgc-1α gene
within human skeletal muscles from subjects with impaired glucose tolerance
or type 2 diabetes. The significance and implications of this discovery are
discussed.
PGC-1α is a transcription coactivator of functional importance in the regulation of
metabolism and other biological processes (1-4). A recent study by Barrès et al. in
Cell Metabolism points to another new role of the Pgc-1α gene regulation in
mitochondrial maintenance and metabolic homeostasis (5). The results showed
significant increases of DNA methylation within the promoter region of the Pgc-1α
gene in human skeletal muscles from subjects with impaired glucose tolerance or
type 2 diabetes. Increased DNA methylation was detected in the promoter region
between -337 and -37 from the transcription start site containing the consensus
binding site for CREB and ATF2 transcription factors. Of particular note is that the
enhanced methylation occurred primarily at non-CpG sites, which in turn led to
reduced Pgc-1α transcription and mitochondrial density. The investigators further
demonstrated that treatment of human skeletal muscle culture with free fatty acids
and tumor necrosis factor-α (TNF-α) for 48 hours reproduced the hypermethylation
Mitochondrial maintenance & PGC-1alpha
of the Pgc-1α promoter through DNA methyltransferase 3B (DNMT3B).
The experiment that demonstrated the direct link between levels of DNA
methylation and Pgc-1α transcription was the reduced reporter gene activity in
transfected muscle cells following in vitro methylation of the promoter at the CpG
site at –260. Although mutation of each or all of the non-CpG sites to prove the
importance of non-CpG methylation may not be technically feasible,
pharmacological inhibition and promotion of methylation could be employed in
cultured myocytes to address this important issue. Precedents have been set in
studies in which maternal nutrient supplementation altered fetal epigenome and the
coat color of the offspring and their susceptibility to obesity and type 2 diabetes
(6,7). It would of great interest to know if dietary interventions would result in
changes in non-CpG methylation in the Pgc-1α gene, which is responsible for the
adult disease susceptibility phenotype, whereas methylation of the CpG sites within
the Avy intracisternal A particle (IAP) retrotransposon of the Agouti gene is known
to be responsible for the agouti color coat phenotype. A genetic approach to alter the
level of expression or enzymatic activity of DNMT3B within skeletal muscle may
also provide additional functional information regarding the epigenetic regulation of
the Pgc-1α gene in vivo. Hypermethylation at non-CpG sites within the Pgc-1α
promoter appeared to occur rapidly during the methylation process, which questions
the long-term impact and significance of non-CpG methylation. This issue is not
only relevant in cultured cell models where DNA methylation and its impact upon
gene expression may be assessed following withdraw of the stimulus, but also in the
situation where its impact may persist over generations in animal models and
humans.
Previous studies have revealed a great diversity in the regulation of PGC-1α
function in decoding various cellular signals and controlling the phenotypic
characteristics of various organ systems. For example, PGC-1α activity has been
shown to be regulated by post-translational modification through phosphorylation
(8), methylation (9), SUMOylation (10), and deacetylation (11). The Pgc-1α gene is
also regulated at the transcriptional level by transcriptional control with an autoregulatory loop (12). Functionally, reduced Pgc-1α gene expression has been shown
to be associated with conditions of insulin resistance and type 2 diabetes (13), and a
missense mutation of the Pgc-1α gene that leads to reduced expression of PGC-1α
has been shown to be correlated with type 2 diabetes in certain populations (14-17).
More recently, attentions have been directed toward epigenetic regulation of the Pgc1α gene (5,18,19). The fact that variants of the Pgc-1α gene were only correlated
with type 2 diabetes in certain population may suggest an environment-gene
Mitochondrial maintenance & PGC-1alpha
interaction in the development of complex diseases in which genetic variation and
environmental factors both contribute to the pathogenesis. Our challenge is not only
to figure out how to apply this knowledge, but also to be prepared to learn of and
from the ‘tricks’ inherent within our biological system to enable us to treat and
prevent complex disease such as type 2 diabetes metillus.
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