Rheostat Control of Gene Expression by Metabolites

Ladurner, Andreas G.

doi:10.1016/j.molcel.2006.09.002

Cited by 81 publications

(68 citation statements)

References 97 publications

(106 reference statements)

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“…What activities might macrodomains bring to macroH2A function? One very appealing possibility is that they function as metabolic sensors by binding specific metabolites or signaling molecules (49). This idea seems consistent with our discovery that macroH2A knockouts have specific effects on the expression of genes related to metabolism and metabolic regulation.…”

Section: Discussionsupporting

confidence: 79%

Mice without MacroH2A Histone Variants

Pehrson

Changolkar

Costanzi

et al. 2014

Molecular and Cellular Biology

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MacroH2A core histone variants have a unique structure that includes a C-terminal nonhistone domain. They are highly conserved in vertebrates and are thought to regulate gene expression. However, the nature of genes regulated by macroH2As and their biological significance remain unclear. Here, we examine macroH2A function in vivo by knocking out both macroH2A1 and macroH2A2 in the mouse. While macroH2As are not required for early development, the absence of macroH2As impairs prenatal and postnatal growth and can significantly reduce reproductive efficiency. The distributions of macroH2A.1-and macroH2A.2-containing nucleosomes show substantial overlap, as do their effects on gene expression. Our studies in fetal and adult liver indicate that macroH2As can exert large positive or negative effects on gene expression, with macroH2A.1 and macroH2A.2 acting synergistically on the expression of some genes and apparently having opposing effects on others. These effects are very specific and in the adult liver preferentially involve genes related to lipid metabolism, including the leptin receptor. MacroH2A-dependent gene regulation changes substantially in postnatal development and can be strongly affected by fasting. We propose that macroH2As produce adaptive changes to gene expression, which in the liver focus on metabolism. MacroH2A core histone variants have a unique structure in which an N-terminal H2A domain is connected to a C-terminal nonhistone domain (1). The H2A domain can substitute for conventional H2A in the nucleosome, and we estimated that ϳ1 in 30 nucleosomes contains a macroH2A in adult rat liver (1, 2), an organ with relatively high macroH2A content. Most of the nonhistone region consists of an evolutionarily conserved domain (3) called a macrodomain. Macrodomains are found in a variety of proteins and as stand-alone proteins in many bacteria (3, 4). Some, but not all, macrodomains bind ADP-ribose with high affinity (5, 6).MacroH2As show a complex distribution in metazoan organisms (7). The basal metazoan species Trichoplax adhaerens and the sponge Amphimedon queenslandica have a macroH2A gene, as does Hydra magnipapillata, clearly indicating its presence in early metazoan evolution. While some other invertebrate genomes contain a macroH2A gene, many complete or nearly complete invertebrate genomes lack macroH2A: e.g., macroH2A is present in a sea urchin (Strongylocentrotus purpuratus), a tick (Ixodes scapularis), and an annelid (Capitella teleta) but is absent in sequenced insects, a nematode (Caenorhabditis elegans), and a tunicate (Ciona intestinalis). Two highly conserved macroH2A genes, macroH2A1 and macroH2A2, are found in mammalian genomes, and clearly homologous genes can be found in birds, reptiles, and fish. To our knowledge, macroH2A genes have not been detected in fungal, protozoan, or plant genomes. These findings indicate that macroH2As first appeared in early metazoan evolution and were lost in some invertebrate lineages but were strongly retained in higher vertebrate species.In mice, hu...

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Section: Discussionsupporting

confidence: 79%

Mice without MacroH2A Histone Variants

Pehrson

Changolkar

Costanzi

et al. 2014

Molecular and Cellular Biology

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“…Moreover, it has become increasingly evident that many protein sensors have evolved to finely sense and respond to the metabolic state of a cell (29). As such, a variety of cellular and metabolic processes will appear to be intimately coupled to these cyclic changes in metabolic state.…”

Section: Discussionmentioning

confidence: 99%

Cyclic changes in metabolic state during the life of a yeast cell

Mohler²,

Liu

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

235

281

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Budding yeast undergo robust oscillations in oxygen consumption during continuous growth in a nutrient-limited environment. Using liquid chromatography-mass spectrometry and comprehensive 2D gas chromatography-mass spectrometry-based metabolite profiling methods, we have determined that the intracellular concentrations of many metabolites change periodically as a function of these metabolic cycles. These results reveal the logic of cellular metabolism during different phases of the life of a yeast cell. They may further indicate that oscillation in the abundance of key metabolites might help control the temporal regulation of cellular processes and the establishment of a cycle. Such oscillations in metabolic state might occur during the course of other biological cycles.gas chromatography-mass spectrometry ͉ liquid chromatography-mass spectrometry ͉ metabolic cycle ͉ metabolite profiling C ircadian rhythms are driven by biological clocks found in virtually all kingdoms of life (1, 2). Genome-wide expression studies in plants, flies, and mice have shown that many genes are expressed periodically as a function of the circadian cycle (3-6). It is now predictable from studies of oscillating gene expression that the circadian regulatory apparatus should differentially control metabolic state as a function of the circadian cycle (7,8). By contrast, direct and comprehensive measurements of changes in sentinel metabolites have not been performed as a function of the circadian cycle or of biological cycles of other temporal dimensions.The budding yeast Saccharomyces cerevisiae exhibits various modes of oscillatory behavior during continuous growth (9-12). We recently established a continuous culture system that reveals an Ϸ4-to 5-h yeast metabolic cycle (YMC) in which over half of the genome is periodically expressed as a function of robust recurring oscillations in oxygen consumption (12). Expression profiling studies have led to the prediction that a variety of cellular and metabolic processes are temporally orchestrated around three major phases of the YMC [oxidative (Ox), reductive/building (RB), and reductive/ charging (RC)] (12). Cells undergoing the YMC are furthermore synchronized with respect to the cell cycle, because the YMC strictly gates cell division to the RB phase when respiration decreases significantly (12).A prediction of temporal compartmentalization is that the concentrations of critical metabolites might exhibit periodic fluctuation and, in turn, play a reciprocal role in regulating the YMC (8). To determine whether cyclic changes in metabolic state might occur during the YMC, we used both liquid chromatography (LC)/ tandem mass spectrometry (LC-MS/MS) and comprehensive 2D gas chromatography (GC)/time-of-f light mass spectrometry (GCϫGC-TOFMS) to monitor the intracellular concentrations of Ϸ150 common metabolites at regularly spaced intervals throughout the YMC. The combined use of LC-MS-and GC-MS-based methods provides a means to evaluate the consistency of results for metabolites detected by both ...

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“…For its deacetylase activity, SIRT1 is strictly dependent on cellular NAD ϩ levels, which reflect cellular energy status. Also the activity of acetyltransferases, such GCN5, that use acetyl-CoA as substrate, is coupled to the metabolic state of the cells (22). Like changes in cellular NAD ϩ levels, that affect SIRT1 deacetylase activity (20), variations in acetyl-CoA substrates for acetyltransferases (22), can therefore lead to changes in histone and protein acetylation, that impact on transcription (23).…”

Section: Discussionmentioning

confidence: 99%

“…Also the activity of acetyltransferases, such GCN5, that use acetyl-CoA as substrate, is coupled to the metabolic state of the cells (22). Like changes in cellular NAD ϩ levels, that affect SIRT1 deacetylase activity (20), variations in acetyl-CoA substrates for acetyltransferases (22), can therefore lead to changes in histone and protein acetylation, that impact on transcription (23). The relative activity of acetyltransferases and deacetylases therefore informs PGC-1␣ about the cellular energy status, which then adapts cellular energy production through its commanding role on mitochondrial biogenesis and function.…”

Section: Discussionmentioning

confidence: 99%

The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1α

Coste

Louet

Lagouge

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

185

169

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Transcriptional control of metabolic circuits requires coordination between specific transcription factors and coregulators and is often deregulated in metabolic diseases. We characterized here the mechanisms through which the coactivator SRC-3 controls energy homeostasis. SRC-3 knock-out mice present a more favorable metabolic profile relative to their wild-type littermates. This metabolic improvement in SRC-3 ؊/؊ mice is caused by an increase in mitochondrial function and in energy expenditure as a consequence of activation of PGC-1␣. By controlling the expression of the only characterized PGC-1␣ acetyltransferase GCN5, SRC-3 induces PGC-1␣ acetylation and consequently inhibits its activity. Interestingly, SRC-3 expression is induced by caloric excess, resulting in the inhibition of PGC-1␣ activity and energy expenditure, whereas caloric restriction reduces SRC-3 levels leading to enhanced PGC-1␣ activity and energy expenditure. Collectively, these data suggest that SRC-3 is a critical link in a cofactor network that uses PGC-1␣ as an effector to control mitochondrial function and energy homeostasis.acetyltransferase ͉ caloric restriction ͉ cofactors ͉ deacetylase ͉ SIRT1

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Rheostat Control of Gene Expression by Metabolites

Cited by 81 publications

References 97 publications

Mice without MacroH2A Histone Variants

Mice without MacroH2A Histone Variants

Cyclic changes in metabolic state during the life of a yeast cell

The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1α

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