Within nucleosomes, canonical histones package the genome, but they can be opportunely replaced with histone variants. The incorporation of histone variants into the nucleosome is a chief cellular strategy to regulate transcription and cellular metabolism. In pathological terms, cellular steatosis is an abnormal accumulation of lipids, which reflects impairment in the turnover of triacylglycerols, affecting any organ but mainly the liver. The present review aims to summarize the experimental evidence for histone variant functions in lipid metabolism.

Introduction

Canonical histones (H2A, H2B, H3 and H4) are assembled into nucleosomes during DNA replication to package it into chromatin. In contrast, histone variants are deposited independently of replication at particular loci of chromosomes. Histone variants participate in DNA repair, gene regulation and other processes that are not fully understood. Their dynamic behaviour and lineage specificity reflect a long evolutionary history that goes from single-celled micro-organisms (Archaea) to humans [1]. Energetic homoeostasis and handling of nutrients is a fundamental function of every cell type. In mammals, cellular steatosis is an excessive accumulation of lipids, which reflects an impairment of the normal processes of synthesis and elimination of triacylglycerol fat. Excess lipid accumulates in vesicles that displace the cytoplasm. Although not particularly detrimental in mild cases, large accumulations can disrupt cell constituents and predispose to severe lipotoxicity and evolve to fibrotic states. As the liver is the primary organ of lipid metabolism, it is most often associated with steatosis; however, it may occur in any organ, particularly the kidneys, pancreas, heart and muscle [2]. Histone variants and post-translational modifications (PTMs) have recently emerged as important epigenetic regulators of lipid turnover and energy homoeostasis in various tissues. Epigenetic changes related to histone variants are involved in human diseases such as obesity, diabetes and the metabolic syndrome. The present review aims specifically to summarize the state-of-the-art knowledge about histone variant functions in lipid metabolism.

Histone variants

The basic repeating unit of the chromatin is the nucleosome that comprises 146 bp of DNA wrapped in a superhelical turn around an octamer of histone core proteins (H2, H3 and H4). Canonical histones package genomic DNA and represent the first level of chromatin organization. The binding of the histone H1 allows the second level of compaction [3]. Although chromatin allows for compaction of large genomes, it also makes DNA inaccessible to factors that remodel nucleosomes. Mechanisms have evolved to regulate and control DNA packaging, allowing chromatin plasticity to ensure the binding of transcriptional factors and maintain cell-type-specific gene expression patterns: nucleosome remodelling enzymes, histone PTMs, and, relevant to this review, the incorporation and exchange of canonical histones with histone variants. Known histone variants belong to the H1, H2 and H3 histone families [1], and give a further grade of complexity to chromatin, fundamental to establish the functional specialization of the cell. Unlike canonical histones that mainly regulate the DNA compaction and transcription process, histone variants participate in a range of processes, including chromosome segregation, DNA repair, transcription initiation and termination and X chromosome inactivation [1]. Histone variants provide a continuous source to nucleosome turnover across their entire lifespan, in addition to being expressed in terminally differentiated cells. In vertebrates, there are multiple copies of canonical histone genes and their protein products are conserved during evolution. Canonical histones assembling on the chromatin take place in the S-phase of the cell cycle. Although canonical histones are the slowest evolving proteins known, variants can have significant differences in primary sequence and some of them with distinct biophysical characteristics. Variants are usually present as single/low-copy genes, for which expression not only is not restricted to the S-phase, but also takes place throughout the cell cycle [1]. The H2A family contains the most known variants, including canonical H2A, H2A.Z, macroH2A, H2A.Bbd and H2A.X, which exhibit variability in amino acid sequence [4]. H2A.Z deposition/eviction at specific loci occurs during the rapid start of transcription, and it was shown to be critical for genome expression and maintenance [5]. H2A.X is characterized by the unique (SQ)(E/D)(I/L/F/Y) motif protruding from its C-terminus, where the serine residue can be phosphorylated in response to the stress of double-strand breaks (DSBs) [4]. MacroH2A1 and macroH2A2 were first described 20 years ago [6] and implicated in X chromosome inactivation [7], and have since fascinated researchers because of their metabolite-sensing function in the non-histone domain [8]. H2A.Bbd expression is restricted to testis and brain [4]. The H3 histone variant family is characterized by replication-dependent H3 histones (H3.1 and H3.2) as well as replication-independent histone H3 variants (H3t, H3.3, CENP-A, H3.X, H3.Y and H3.5) [1]. Despite sequence homology, H3 variants show large differences in their localization in the chromatin [9]. Several functional properties of H3 variants are associated with PTMs and occur in the context of heterochromatin formation. H3.3 histone variant is constitutively expressed throughout the cell cycle [9a], and it is enriched across the gene body of both active and inactive genes [1012].

Cellular steatosis: epigenetic control

The epigenetic level of transcriptional control, such as DNA methylation and PTM, is gaining acceptance in the pathophysiology of several diseases featuring an imbalance in lipid homoeostasis, such as non-alcoholic fatty liver disease (NAFLD). Mounting evidence suggests that cellular epigenetic modifications may be a predetermining factor to individual susceptibilities to the condition [13,14]. Epigenetic modifications are inherited and provide a flexible interface between the organism and its environment [15]. Although most common metabolic diseases and multiple cancers present with heritable traits, they do not follow classical Mendelian inheritance. The complex outcome of these diseases has been attributed to epigenetic changes in response to the environment [15,16]. Moreover, there is evidence for transgenerational epigenetic effects including metabolic and nutrient homoeostasis disturbances [1719]. Although in most cases the molecular mechanism of inheritance is not understood, recent evidence suggests that diffusible factors and chromatin marks, including histone variants, seem to be an attractive candidate that promotes epigenetic changes [20]. The potential role of epigenetics beyond gene regulation in the intergenerational heritability is only recently beginning to emerge. Most of the heritable changes are established during differentiation and are maintained through multiple cycles of cell division, enabling cells to have different entities while containing the same genetic information. The heritability of the gene expression pattern is mediated by epigenetic modifications that include DNA methylation, PTMs of histone proteins and RNA-mediated gene silencing. Histone modifications are maintained through cell division and distinct histone modifications, on one or more tails, act sequentially or in combination to form a ‘histone code’ [21]. This code is read by other proteins bringing about distinct downstream events, dictating disease outcomes linked to alterations in lipid metabolism [22]. During the occurrence of cellular steatosis, such as in NAFLD, several epigenetic alterations may concur. In mice, hepatic steatosis was accompanied by loss of genomic cytosine methylation, through aberrant histone modifications and alterations in expression of the DNA methyltransferase 1 (DNMT1) and DNMT3A proteins in the liver [13]. Epigenetic phenotype may predetermine individual susceptibility to cellular steatosis. We have shown that mouse offspring, born to high-fat-fed mothers, display increased fat in the liver and in the pancreas [17,18,23]. Intriguingly, rodent studies suggest that the offspring from high-fat-fed fathers are also prone to develop fat-related disorders, suggesting that intergenerational transmission of metabolic traits such as NAFLD may persist through epigenetic changes in deter-mined genome regions of male gametes [19,24]. Acetylation of histones on lysine residues is altered in genetic murine models of steatosis [25,26]. Loss of acetylation is mediated by the activity of the epigenetic enzymes the histone deacetylases (HDAC): among those there are the sirtuins (SIRTs). There are seven mammalian SIRTs (SIRT1–SIRT7), NAD+-dependent protein deacetylases involved in multiple cellular events including chromatin remodelling, energy metabolism and stress resistance. The most studied member of the family is SIRT1. SIRT1 mediates the beneficial effects of a caloric-restricted dietary regimen, at least in part, from the regulation of energy homoeostasis, circadian rhythms and antioxidant responses in each cell type studied [2729]. Consistently, SIRT1 is an important determinant of lipolysis and fatty acid oxidation in fat-storing tissues. For instance, liver-specific overexpression of SIRT1 significantly attenuates hepatic steatosis [30]. The next section describes the epigenetic role of histone variants in cellular steatosis.

Histone variants and lipid metabolism

Variations in the expression of histone variants have been observed in tissues accumulating fat, in mouse models and human beings (Table 1). MacroH2A histones consist of two members, macroH2A1 and macroH2A2, coded for by different genes and that differ in their tissue-specific patterns of expression [31,32]. In turn, macroH2A1 can give rise to two alternatively exon-spliced isoforms, macroH2A1.1 and macroH2A1.2, which differ in their ability to bind O-acetyl-ADP-ribose (OAADPR), a small metabolite produced by SIRT1 [33,34]. MacroH2A1 isoforms are found to be up-regulated at the protein levels in the liver of mice displaying NAFLD as a simple lipid accumulation or displaying its inflammatory form non-alcoholic steatohepatitis (NASH), induced either by a high-fat diet or by a diet deficient in methionine and choline [13,35]. MacroH2A1.2 is specifically enriched in the liver of NAFLD mouse models, compared with macroH2A1.1 [35]. Both macroH2A1 isoforms are massively up-regulated in cryptogenic (i.e. without a known pathogenesis) hepatocellular carcinoma (HCC) developing on a steatotic background in humans [35]. The expression of H2A.X phosphorylated on Ser139, γH2A.X, is found increased in NAFLD/NASH in mice [36] and humans [37], indicating increased DNA damage and DSBs. with the accumulation of lipid into the liver, although this is controversial [38]. These correlative/associative studies indicate a possible conserved involvement of histone variants, and in particular macroH2A1 isoforms, in lipid metabolism. A number of mechanistic studies have explored this possibility (Table 2). Two mouse models with a macroH2A1 knockout have been reported under a standard diet feeding. In the first model, generated in the pure C57Bl/6J background, developmental changes in macroH2A1-mediated gene regulation were observed [39,40]: up-regulation of lipogenic genes such as CD36, lipoprotein lipase and serpin was detected in the liver of the knockout mice [39], which displayed slight systemic glucose intolerance in the male sex [39]. NAFLD was not observed. This proposed link between lipogenic gene expression in the liver and systemic glucose intolerance is quite surprising since 80–90% of the glucose is taken up by the skeletal muscle, rather than by the liver. The changes in lipogenic gene expression have subsequently been associated with differential physical occupancy of the gene body by macroH2A1 [40]. In the second model, knockout of macroH2A1 in a mixed background led to a variable hepatic lipid accumulation in 50% of the females [41]. In this model, the X-linked thyroxine-binding globulin (Tbg) gene was found to be up-regulated in steatotic livers. Tbg is the main carrier of the thyroid hormone T4 (thyroxine), a major regulator of energy metabolism, which could be responsible for the enhanced fat accumulation. Enrichment of macroH2A1 at the Tbg promoter in female animals indicated that increased Tbg expression in macroH2A1-knockout mice could be a direct consequence of the absence of this histone [41]. The sexual dimorphism of the NAFLD phenotype is possibly due to the different incorporation of macroH2A1 between the two sexes. We have recently studied in the hepatoma cell lines Hepa1-6 (mouse) and HepG2 (human) whether the two splicing variants of macroH2A1, macroH2A1.1 and macroH2A1.2, might have different roles in lipid accumulation (Table 2). Our biochemical and quantitative imaging analyses showed that ectopic overexpression of macroH2A1.1, but not of macroH2A1.2, is able to protect hepatoma cells against lipid accumulation, both triacylglycerols and cholesterol [42]. MacroH2A1.1-overexpressing cells display ameliorated glucose metabolism, reduced expression of lipogenic genes and fatty acid content [42]. Moreover, macroH2A1.1 consistently decreases the formation of membrane unsaturated fatty acids in the two hepatoma cell lines [42]. Since macroH2A1.1 binds OAADPR produced by SIRT1, it is plausible that this epigenetic regulation of lipid metabolism may be relevant to NAFLD development. Recent studies indicate that another variant of histone H2A, H2A.Z, is crucial in adipogenesis, the process by which pre-adipocytes differentiate into fat cells, mature adipocytes. 3T3-L1 pre-adipocytes silenced for H2A.Z expression fail to differentiate in mature adipocytes and accumulate fat [43]. Recently, an inverse relationship between macroH2A1 and H2A.Z in occupancy of the promoter regions of tumour-suppressor genes has been demonstrated [44]: it would be interesting to assess the role of this physical exchange on the body of genes involved in lipid turnover. Of note, genome-wide studies accompanied by quantitative imaging demonstrated that histone variant H3.3, which in contrast with its canonical counterpart H3 is incorporated into the chromatin in a replication-independent manner, is enriched at promoters of genes, which enforce the adipogenic differentiation of mesenchymal stem cells [45]. H2A histone variants have also been reported to influence lipid accumulation in lower simpler organisms (Table 2). In a yeast strain genetically knocked out for H2A.Z, transcriptional blockage of genes which are necessary for the metabolic response to incubation with oleic acid has been observed [46]. In the fruitfly Drosophila melanogaster there exists a molecular machinery involving a protein called Jabba that recruits histones and the histone variant H2A.v to lipid droplets during embryonic development [47]. The physical affinity between histone and histone variants in Drosophila has been interpreted as a mechanism by which the embryos build up extranuclear histone stores and provides them for chromatin assembly when needed [47].

Table 1
Altered expression of histone variants associated with diseases of hepatic lipid homoeostasis
Histone variant Species Disease Up-regulation/down-regulation Reference 
MacroH2A Mouse NASH Up-regulation [13
MacroH2A1.1 Mouse NASH/HCC – [35
MacroH2A1.2 Mouse NASH/HCC Up-regulation [35
MacroH2A1.1 Human NAFLD/HCC Up-regulation [35
MacroH2A1.2 Human NAFLD/HCC Up-regulation [35
γH2A.X Human NAFLD Up-regulation [37
γH2A.X Human NASH Down-regulation [38
γH2A.X Mouse NASH Up-regulation [36
Histone variant Species Disease Up-regulation/down-regulation Reference 
MacroH2A Mouse NASH Up-regulation [13
MacroH2A1.1 Mouse NASH/HCC – [35
MacroH2A1.2 Mouse NASH/HCC Up-regulation [35
MacroH2A1.1 Human NAFLD/HCC Up-regulation [35
MacroH2A1.2 Human NAFLD/HCC Up-regulation [35
γH2A.X Human NAFLD Up-regulation [37
γH2A.X Human NASH Down-regulation [38
γH2A.X Mouse NASH Up-regulation [36
Table 2
Effects of manipulating histone variants expression on lipid homoeostasis
Histone variant Model Treatment Overexpression (OE) or knockout (KO) Phenotype Reference(s) 
MacroH2A1 Mouse – KO Glucose intolerance, increased hepatic lipidogenic gene expression [39,40
MacroH2A1 Mouse – KO Fatty liver in 50% of females; overexpression of the X-linked thyroxine-binding globulin gene [41
MacroH2A1.1 Hepatoma cells Fatty acids OE Antilipidogenic [42
MacroH2A1.2 Hepatoma cells Fatty acids OE Prolipidogenic [42
H2A.Z 3T3-L1 cells Differentiation into adipocytes KO Abrogation of adipogenic differentiation [43
H2A.Z Yeast Oleic acid KO Transcriptional inactivation of a subset of oleic acid-responsive genes [46
H3.3 Mesenchymal stem cells – OE Enrichment in the promoter of genes involved in adipogenesis [45
H2A.v Drosophila KO for Jabba – Depletion from embryonic lipid droplets [47
Histone variant Model Treatment Overexpression (OE) or knockout (KO) Phenotype Reference(s) 
MacroH2A1 Mouse – KO Glucose intolerance, increased hepatic lipidogenic gene expression [39,40
MacroH2A1 Mouse – KO Fatty liver in 50% of females; overexpression of the X-linked thyroxine-binding globulin gene [41
MacroH2A1.1 Hepatoma cells Fatty acids OE Antilipidogenic [42
MacroH2A1.2 Hepatoma cells Fatty acids OE Prolipidogenic [42
H2A.Z 3T3-L1 cells Differentiation into adipocytes KO Abrogation of adipogenic differentiation [43
H2A.Z Yeast Oleic acid KO Transcriptional inactivation of a subset of oleic acid-responsive genes [46
H3.3 Mesenchymal stem cells – OE Enrichment in the promoter of genes involved in adipogenesis [45
H2A.v Drosophila KO for Jabba – Depletion from embryonic lipid droplets [47

Conclusions

Histone variants appeared richly during evolution to contribute to a distinct or unique nucleosomal architecture. This heterogeneity can be exploited to modulate a wide range of nuclear dynamic functions. Lipid accumulation in specialized cells or tissues, from lower to higher organisms, provides a fundamental solution to store energy important for development or for times of need. Growing evidence shows that histone variants of canonical histones H2A and H3 are able to influence lipogenic gene expression by promoter and/or gene body occupancy. In the case of macroH2A1, it is believed that it might directly transduce metabolic signals to the nucleosomes by binding small metabolites. Whereas much emphasis relies traditionally on the study of histone PTMs in cell metabolism, a deeper understanding of the elegant layer of epigenetic regulation provided by histone variants might have implications for health and disease.

Membrane Morphology and Function: A Biochemical Society Focused Meeting held at Hotel del Camerlengo, Fara San Martino, Abruzzo, Italy, 5–8 May 2014. Organized and Edited by Banafshé Larijani [IKERBASQUE, Basque Foundation for Science and Unidad de Biofísica (CSIC-UPV/EHU), University of the Basque Country, Spain] and Marco Falasca (Barts and The London School of Medicine and Dentistry, U.K.)

Abbreviations

     
  • DNMT

    DNA methyltransferase

  •  
  • DSB

    double-strand break

  •  
  • HCC

    hepatocellular carcinoma

  •  
  • NAFLD

    non-alcoholic fatty liver disease

  •  
  • NASH

    non-alcoholic steatohepatitis

  •  
  • OAADPR

    O-acetyl-ADP-ribose

  •  
  • PTM

    post-translational modification

  •  
  • SIRT

    sirtuin

  •  
  • Tbg

    thyroxine-binding globulin

We acknowledge and apologize to all the scientists bringing important contributions that were not cited owing to a lack of space or oversight.

Funding

M.V. is a recipient of a My First AIRC Grant from Associazione Italiana per la Ricerca sul Cancro, Italy.

References

References
1
Talbert
P.B.
Henikoff
S.
Histone variants: ancient wrap artists of the epigenome
Nat. Rev. Mol. Cell Biol.
2010
, vol. 
11
 (pg. 
264
-
275
)
[PubMed]
2
Cotran
RS.
Kumar
V.
Collins
T.
Robbins Pathologic Basis of Disease
1998
6th edn
Philadelphia
W.B. Saunders Company
3
Li
G.
Reinberg
D.
Chromatin higher-order structures and gene regulation
Curr. Opin. Genes Dev.
2011
, vol. 
21
 (pg. 
175
-
186
)
4
Millar
C.B.
Organizing the genome with H2A histone variants
Biochem. J.
2013
, vol. 
449
 (pg. 
567
-
579
)
[PubMed]
5
Billon
P.
Cote
J.
Precise deposition of histone H2A.Z in chromatin for genome expression and maintenance
Biochim. Biophys. Acta
2012
, vol. 
1819
 (pg. 
290
-
302
)
6
Pehrson
J.R.
Fried
V.A.
MacroH2A, a core histone containing a large nonhistone region
Science
1992
, vol. 
257
 (pg. 
1398
-
1400
)
[PubMed]
7
Costanzi
C.
Pehrson
J.R.
Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals
Nature
1998
, vol. 
393
 (pg. 
599
-
601
)
[PubMed]
8
Timinszky
G.
Till
S.
Hassa
P.O.
Hothorn
M.
Kustatscher
G.
Nijmeijer
B.
Colombelli
J.
Altmeyer
M.
Stelzer
E.H.
Scheffzek
K.
, et al. 
A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation
Nat. Struct. Mol. Biol.
2009
, vol. 
16
 (pg. 
923
-
929
)
[PubMed]
9
Kurumizaka
H.
Horikoshi
N.
Tachiwana
H.
Kagawa
W.
Current progress on structural studies of nucleosomes containing histone H3 variants
Curr. Opin. Struct. Biol.
2013
, vol. 
23
 (pg. 
109
-
115
)
[PubMed]
9a
Szenker
E.
Ray-Gallet
D.
Almouzni
G.
The double face of the histone variant H3.3
Cell Res.
2011
, vol. 
21
 (pg. 
421
-
434
)
[PubMed]
10
Goldberg
A.D.
Banaszynski
L.A.
Noh
K.M.
Lewis
P.W.
Elsaesser
S.J.
Stadler
S.
Dewell
S.
Law
M.
Guo
X.
Li
X.
, et al. 
Distinct factors control histone variant H3.3 localization at specific genomic regions
Cell
2010
, vol. 
140
 (pg. 
678
-
691
)
[PubMed]
11
Chow
C.M.
Georgiou
A.
Szutorisz
H.
Maia e Silva
A.
Pombo
A.
Barahona
I.
Dargelos
E.
Canzonetta
C.
Dillon
N.
Variant histone H3.3 marks promoters of transcriptionally active genes during mammalian cell division
EMBO Rep.
2005
, vol. 
6
 (pg. 
354
-
360
)
[PubMed]
12
Mito
Y.
Henikoff
J.G.
Henikoff
S.
Genome-scale profiling of histone H3.3 replacement patterns
Nat. Genet.
2005
, vol. 
37
 (pg. 
1090
-
1097
)
[PubMed]
13
Pogribny
I.P.
Tryndyak
V.P.
Bagnyukova
T.V.
Melnyk
S.
Montgomery
B.
Ross
S.A.
Latendresse
J.R.
Rusyn
I.
Beland
F.A.
Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet
J. Hepatol.
2009
, vol. 
51
 (pg. 
176
-
186
)
[PubMed]
14
Podrini
C.
Borghesan
M.
Greco
A.
Pazienza
V.
Mazzoccoli
G.
Vinciguerra
M.
Redox homeostasis and epigenetics in non-alcoholic fatty liver disease (NAFLD)
Curr. Pharm. Des.
2013
, vol. 
19
 (pg. 
2737
-
2746
)
[PubMed]
15
Feinberg
A.P.
Phenotypic plasticity and the epigenetics of human disease
Nature
2007
, vol. 
447
 (pg. 
433
-
440
)
[PubMed]
16
Feinberg
A.P.
Epigenetics at the epicenter of modern medicine
JAMA
2008
, vol. 
299
 (pg. 
1345
-
1350
)
[PubMed]
17
Mouralidarane
A.
Soeda
J.
Visconti-Pugmire
C.
Samuelsson
A.M.
Pombo
J.
Maragkoudaki
X.
Butt
A.
Saraswati
R.
Novelli
M.
Fusai
G.
, et al. 
Maternal obesity programs offspring non-alcoholic fatty liver disease via innate immune dysfunction in mice
Hepatology
2013
, vol. 
58
 (pg. 
128
-
138
)
[PubMed]
18
Oben
J.A.
Mouralidarane
A.
Samuelsson
A.M.
Matthews
P.J.
Morgan
M.L.
McKee
C.
Soeda
J.
Fernandez-Twinn
D.S.
Martin-Gronert
M.S.
Ozanne
S.E.
, et al. 
Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice
J. Hepatol.
2010
, vol. 
52
 (pg. 
913
-
920
)
[PubMed]
19
Zeybel
M.
Hardy
T.
Wong
Y.K.
Mathers
J.C.
Fox
C.R.
Gackowska
A.
Oakley
F.
Burt
A.D.
Wilson
C.L.
Anstee
Q.M.
, et al. 
Multigenerational epigenetic adaptation of the hepatic wound-healing response
Nat. Med.
2012
, vol. 
18
 (pg. 
1369
-
1377
)
[PubMed]
20
Daxinger
L.
Whitelaw
E.
Understanding transgenerational epigenetic inheritance via the gametes in mammals
Nat. Rev. Genet.
2012
, vol. 
13
 (pg. 
153
-
162
)
[PubMed]
21
Taverna
S.D.
Li
H.
Ruthenburg
A.J.
Allis
C.D.
Patel
D.J.
How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers
Nat. Struct. Mol. Biol.
2007
, vol. 
14
 (pg. 
1025
-
1040
)
[PubMed]
22
Lennartsson
A.
Ekwall
K.
Histone modification patterns and epigenetic codes
Biochim. Biophys. Acta
2009
, vol. 
1790
 (pg. 
863
-
868
)
[PubMed]
23
Carter
R.
Mouralidarane
A.
Soeda
J.
Ray
S.
Pombo
J.
Saraswati
R.
Novelli
M.
Fusai
G.
Rappa
F.
Saracino
C.
, et al. 
Non-alcoholic Fatty pancreas disease pathogenesis: a role for developmental programming and altered circadian rhythms
PLoS ONE
2014
, vol. 
9
 pg. 
e89505
 
[PubMed]
24
Curley
J.P.
Mashoodh
R.
Champagne
F.A.
Epigenetics and the origins of paternal effects
Horm. Behav.
2011
, vol. 
59
 (pg. 
306
-
314
)
[PubMed]
25
Purushotham
A.
Schug
T.T.
Xu
Q.
Surapureddi
S.
Guo
X.
Li
X.
Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation
Cell Metab.
2009
, vol. 
9
 (pg. 
327
-
338
)
[PubMed]
26
Feng
D.
Liu
T.
Sun
Z.
Bugge
A.
Mullican
S.E.
Alenghat
T.
Liu
X.S.
Lazar
M.A.
A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism
Science
2011
, vol. 
331
 (pg. 
1315
-
1319
)
[PubMed]
27
Guarente
L.
Franklin H. Epstein Lecture: sirtuins, aging, and medicine
N. Engl. J. Med.
2011
, vol. 
364
 (pg. 
2235
-
2244
)
[PubMed]
28
Vinciguerra
M.
Santini
M.P.
Claycomb
W.C.
Ladurner
A.G.
Rosenthal
N.
Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity
Aging
2010
, vol. 
2
 (pg. 
43
-
62
)
29
Vinciguerra
M.
Santini
M.P.
Martinez
C.
Pazienza
V.
Claycomb
W.C.
Giuliani
A.
Rosenthal
N.
mIGF-1/JNK1/SirT1 signaling confers protection against oxidative stress in the heart
Aging Cell
2012
, vol. 
11
 (pg. 
139
-
149
)
[PubMed]
30
Li
Y.
Wong
K.
Giles
A.
Jiang
J.
Lee
J.W.
Adams
A.C.
Kharitonenkov
A.
Yang
Q.
Gao
B.
Guarente
L.
Zang
M.
Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21
Gastroenterology
2014
, vol. 
146
 (pg. 
539
-
549.e7
)
31
Buschbeck
M.
Di Croce
L.
Approaching the molecular and physiological function of macroH2A variants
Epigenetics
2010
, vol. 
5
 (pg. 
118
-
123
)
[PubMed]
32
Cantarino
N.
Douet
J.
Buschbeck
M.
MacroH2A: an epigenetic regulator of cancer
Cancer Lett.
2013
, vol. 
336
 (pg. 
247
-
252
)
[PubMed]
33
Kustatscher
G.
Hothorn
M.
Pugieux
C.
Scheffzek
K.
Ladurner
A.G.
Splicing regulates NAD metabolite binding to histone macroH2A
Nat. Struct. Mol. Biol.
2005
, vol. 
12
 (pg. 
624
-
625
)
[PubMed]
34
Karras
G.I.
Kustatscher
G.
Buhecha
H.R.
Allen
M.D.
Pugieux
C.
Sait
F.
Bycroft
M.
Ladurner
A.G.
The macro domain is an ADP-ribose binding module
EMBO J.
2005
, vol. 
24
 (pg. 
1911
-
1920
)
[PubMed]
35
Rappa
F.
Greco
A.
Podrini
C.
Cappello
F.
Foti
M.
Bourgoin
L.
Peyrou
M.
Marino
A.
Scibetta
N.
Williams
R.
, et al. 
Immunopositivity for histone macroH2A1 isoforms marks steatosis-associated hepatocellular carcinoma
PLoS ONE
2013
, vol. 
8
 pg. 
e54458
 
[PubMed]
36
Pogribny
I.P.
Starlard-Davenport
A.
Tryndyak
V.P.
Han
T.
Ross
S.A.
Rusyn
I.
Beland
F.A.
Difference in expression of hepatic microRNAs miR-29c, miR-34a, miR-155, and miR-200b is associated with strain-specific susceptibility to dietary nonalcoholic steatohepatitis in mice
Lab. Invest.
2010
, vol. 
90
 (pg. 
1437
-
1446
)
[PubMed]
37
Aravinthan
A.
Scarpini
C.
Tachtatzis
P.
Verma
S.
Penrhyn-Lowe
S.
Harvey
R.
Davies
S.E.
Allison
M.
Coleman
N.
Alexander
G.
Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease
J. Hepatol.
2013
, vol. 
58
 (pg. 
549
-
556
)
[PubMed]
38
Schults
M.A.
Nagle
P.W.
Rensen
S.S.
Godschalk
R.W.
Munnia
A.
Peluso
M.
Claessen
S.M.
Greve
J.W.
Driessen
A.
Verdam
F.J.
, et al. 
Decreased nucleotide excision repair in steatotic livers associates with myeloperoxidase-immunoreactivity
Mutat. Res.
2012
, vol. 
736
 (pg. 
75
-
81
)
[PubMed]
39
Changolkar
L.N.
Costanzi
C.
Leu
N.A.
Chen
D.
McLaughlin
K.J.
Pehrson
J.R.
Developmental changes in histone macroH2A1-mediated gene regulation
Mol. Cell. Biol.
2007
, vol. 
27
 (pg. 
2758
-
2764
)
[PubMed]
40
Changolkar
L.N.
Singh
G.
Cui
K.
Berletch
J.B.
Zhao
K.
Disteche
C.M.
Pehrson
J.R.
Genome-wide distribution of macroH2A1 histone variants in mouse liver chromatin
Mol. Cell. Biol.
2010
, vol. 
30
 (pg. 
5473
-
5483
)
[PubMed]
41
Boulard
M.
Storck
S.
Cong
R.
Pinto
R.
Delage
H.
Bouvet
P.
Histone variant macroH2A1 deletion in mice causes female-specific steatosis
Epigenetics Chromatin
2010
, vol. 
3
 pg. 
8
 
[PubMed]
42
Pazienza
V.
Borghesan
M.
Mazza
T.
Sheedfar
F.
Panebianco
C.
Williams
R.
Mazzoccoli
G.
Andriulli
A.
Nakanishi
T.
Vinciguerra
M.
SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation
Aging
2014
, vol. 
6
 (pg. 
35
-
47
)
[PubMed]
43
Couture
J.P.
Nolet
G.
Beaulieu
E.
Blouin
R.
Gevry
N.
The p400/Brd8 chromatin remodeling complex promotes adipogenesis by incorporating histone variant H2A.Z at PPARγ target genes
Endocrinology
2012
, vol. 
153
 (pg. 
5796
-
5808
)
[PubMed]
44
Barzily-Rokni
M.
Friedman
N.
Ron-Bigger
S.
Isaac
S.
Michlin
D.
Eden
A.
Synergism between DNA methylation and macroH2A1 occupancy in epigenetic silencing of the tumor suppressor gene p16(CDKN2A)
Nucleic Acids Res.
2011
, vol. 
39
 (pg. 
1326
-
1335
)
[PubMed]
45
Delbarre
E.
Jacobsen
B.M.
Reiner
A.H.
Sorensen
A.L.
Kuntziger
T.
Collas
P.
Chromatin environment of histone variant H3.3 revealed by quantitative imaging and genome-scale chromatin and DNA immunoprecipitation
Mol. Biol. Cell
2010
, vol. 
21
 (pg. 
1872
-
1884
)
[PubMed]
46
Wan
Y.
Saleem
R.A.
Ratushny
A.V.
Roda
O.
Smith
J.J.
Lin
C.H.
Chiang
J.H.
Aitchison
J.D.
Role of the histone variant H2A.Z/Htz1p in TBP recruitment, chromatin dynamics, and regulated expression of oleate-responsive genes
Mol. Cell. Biol.
2009
, vol. 
29
 (pg. 
2346
-
2358
)
[PubMed]
47
Li
Z.
Thiel
K.
Thul
P.J.
Beller
M.
Kuhnlein
R.P.
Welte
M.A.
Lipid droplets control the maternal histone supply of Drosophila embryos
Curr. Biol.
2012
, vol. 
22
 (pg. 
2104
-
2113
)
[PubMed]