GENÉTICA

Epigenetic Control of rDNA
Loci in Response to
Intracellular Energy Status
Akiko Murayama,1,2,5,6 Kazuji Ohmori,1,6 Akiko Fujimura,1 Hiroshi Minami,4 Kayoko Yasuzawa-Tanaka,1
Takao Kuroda,1 Shohei Oie,1 Hiroaki Daitoku,2 Mitsuru Okuwaki,3 Kyosuke Nagata,3 Akiyoshi Fukamizu,2
Keiji Kimura,1 Toshiyuki Shimizu,4 and Junn Yanagisawa1,*
1Graduate School of Life and Environmental Sciences
2Center for Tsukuba Advanced Research Alliance
3Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences
University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8572, Japan
4International Graduate School of Arts and Sciences, Yokohama City University, Yokohama, Kanagawa 230-0045, Japan
5PRESTO, JST, 4-1-8 Honcho Kawaguchi, Saitama, Japan
6These authors contributed equally to this work.
*Correspondence: junny@agbi.tsukuba.ac.jp
DOI 10.1016/j.cell.2008.03.030
SUMMARY
Intracellular energy balance is important for cell survival.
In eukaryotic cells, the most energy-consuming
process is ribosome biosynthesis, which adapts to
changes in intracellular energy status. However, the
mechanism that links energy status and ribosome
biosynthesis is largely unknown. Here, we describe
eNoSC, a protein complex that senses energy status
and controls rRNA transcription. eNoSC contains
Nucleomethylin, which binds histone H3 dimethylated
Lys9 in the rDNA locus, in a complex with
SIRT1 and SUV39H1. Both SIRT1 and SUV39H1 are
required for energy-dependent transcriptional repression,
suggesting that a change in the NAD+/
NADH ratio induced by reduction of energy status
could activate SIRT1, leading to deacetylation of histone
H3 and dimethylation at Lys9 by SUV39H1, thus
establishing silent chromatin in the rDNA locus. Furthermore,
eNoSC promotes restoration of energy
balance by limiting rRNA transcription, thus protecting
cells from energy deprivation-dependent apoptosis.
These findings provide key insight into the mechanisms
of energy homeostasis in cells.
INTRODUCTION
Ribosome production is a major biosynthetic and energy-consuming
activity of eukaryotic cells. Ribosome biosynthesis
adapts rapidly to changes in intracellular energy status. Conditions
of energy starvation or glucose deprivation—when cellular
AMP/ATP ratio is increased—lead to the activation of the LKB1-
AMPK (AMP-activated protein kinase) pathway (Hardie, 2004);
this signaling inhibits mammalian TOR (target of rapamycin)/
p70 S6 kinase activity, which is required for rapid and sustained
serum-induced ribosome biosynthesis (Bhaskar and Hay, 2007).
Inhibition of mTOR activity by AMPK suppresses energy expenditure
and protects cells from energy deprivation-induced apoptosis
(Inoki et al., 2003; Shaw et al., 2004). Anaerobic conditions
also reduce cellular energy supply. Cells regulate energy demand
by sensing the environmental concentration of hydrogen
ions. H+ produced under hypoxia promotes interactions between
VHL and rDNA to reduce rRNA synthesis (Mekhail et al.,
2006).
rRNA synthesis is tightly regulated in response to metabolic
and environmental changes (Grummt, 2003; Moss et al., 2007).
rRNA genes are present in multiple copies; therefore, rRNA synthesis
could be modulated by varying transcription rate per gene
or by varying the number of active genes. Exponentially growing
cells use no more than half of their total complement of rRNA
genes, and it has been shown in both mammalian cells and budding
yeast that the number of active genes decreases when cells
undergo transition from log to stationary phase (Claypool et al.,
2004; Preuss and Pikaard, 2007; Sandmeier et al., 2002). In
yeast, this gene inactivation is dependent on the histone deacetylase
Rpd3 (Oakes et al., 2006). In mammalian cells, the chromatin-
remodeling complex NoRC recruits HDAC1 and DNA
methyltransferases to inactive rRNA gene repeats (Santoro
et al., 2002). Furthermore, the activity level of rRNA genes is correlated
with the type and extent of their chromatin modifications.
Taken together, these data argue that epigenetic mechanisms
control the ratio of active to inactive genes.
In yeast, heterochromatin formation at the ribosomal DNA
(rDNA) locus is also controlled by Sir2p, an NAD+-dependent deacetylase
that removes acetyl groups from the N-terminal tails of
histone H3 and H4 to regulate nucleosome and chromatin structure
(Buck et al., 2002). Increasing the expression of Sir2p can
extend the life span of yeast by suppressing homologous recombination
between rDNA repeat sequences (Guarente, 2000). In
human, the Sir2p homolog SIRT1 deacetylates transcription
factors such as FOXOs, p53, and NF-kB (Yang et al., 2006).
SIRT1 is inducibly transcribed in response to calorie restriction
Cell 133, 627–639, May 16, 2008 ª2008 Elsevier Inc. 627