Minor Satellites Research Articles

CFDP1 regulates the stability of pericentric heterochromatin thereby affecting RAN GTPase activity and mitotic spindle formation.

The densely packed centromeric heterochromatin at minor and major satellites is comprised of H3K9me2/3 histones, the heterochromatin protein HP1α, and histone variants. In the present study, we sought to determine the mechanisms by which condensed heterochromatin at major and minor satellites stabilized by the chromatin factor CFDP1 affects the activity of the small GTPase Ran as a requirement for spindle formation. CFDP1 colocalized with heterochromatin at major and minor satellites and was essential for the structural stability of centromeric heterochromatin. Loss of CENPA, HP1α, and H2A.Z heterochromatin components resulted in decreased binding of the spindle nucleation facilitator RCC1 to minor and major satellite repeats. Decreased RanGTP levels as a result of diminished RCC1 binding interfered with chromatin-mediated microtubule nucleation at the onset of mitotic spindle formation. Rescuing chromatin H2A.Z levels in cells and mice lacking CFDP1 through knock-down of the histone chaperone ANP32E not only partially restored RCC1-dependent RanGTP levels but also alleviated CFDP1-knockout-related craniofacial defects and increased microtubule nucleation in CFDP1/ANP32E co-silenced cells. Together, these studies provide evidence for a direct link between condensed heterochromatin at major and minor satellites and microtubule nucleation through the chromatin protein CFDP1.

DNA satellite and chromatin organization at mouse centromeres and pericentromeres

BackgroundCentromeres are essential for faithful chromosome segregation during mitosis and meiosis. However, the organization of satellite DNA and chromatin at mouse centromeres and pericentromeres is poorly understood due to the challenges of assembling repetitive genomic regions.ResultsUsing recently available PacBio long-read sequencing data from the C57BL/6 strain, we find that contrary to the previous reports of their homogeneous nature, both centromeric minor satellites and pericentromeric major satellites exhibit a high degree of variation in sequence and organization within and between arrays. While most arrays are continuous, a significant fraction is interspersed with non-satellite sequences, including transposable elements. Using chromatin immunoprecipitation sequencing (ChIP-seq), we find that the occupancy of CENP-A and H3K9me3 chromatin at centromeric and pericentric regions, respectively, is associated with increased sequence enrichment and homogeneity at these regions. The transposable elements at centromeric regions are not part of functional centromeres as they lack significant CENP-A enrichment. Furthermore, both CENP-A and H3K9me3 nucleosomes occupy minor and major satellites spanning centromeric-pericentric junctions and a low yet significant amount of CENP-A spreads locally at centromere junctions on both pericentric and telocentric sides. Finally, while H3K9me3 nucleosomes display a well-phased organization on major satellite arrays, CENP-A nucleosomes on minor satellite arrays are poorly phased. Interestingly, the homogeneous class of major satellites also phase CENP-A and H3K27me3 nucleosomes, indicating that the nucleosome phasing is an inherent property of homogeneous major satellites.ConclusionsOur findings reveal that mouse centromeres and pericentromeres display a high diversity in satellite sequence, organization, and chromatin structure.

DNMT1 Y495C mutation interferes with maintenance methylation of imprinting control regions

Hereditary Sensory and Autonomic Neuropathy Type 1E (HSAN1E) is a rare autosomal dominant neurological disorder due to missense mutations in DNA methyltransferase 1 (DNMT1). To investigate the nature of the dominant effect, we compared methylomes of transgenic R1wtDnmt1 and R1Dnmt1Y495C mouse embryonic stem cells (mESCs) overexpressing WT and the mutant mouse proteins respectively, with the R1 (wild-type) cells. In case of R1Dnmt1Y495C, 15 out of the 20 imprinting control regions were hypomethylated with transcript level dysregulation of multiple imprinted genes in ESCs and neurons. Non-imprinted regions, minor satellites, major satellites, LINE1 and IAP repeats were unaffected. These data mirror the specific imprinting defects associated with transient removal of DNMT1 in mESCs, deletion of the maternal-effect DNMT1o variant in preimplantation mouse embryos, and in part, reprogramming to naïve human iPSCs. This is the first DNMT1 mutation demonstrated to specifically affect Imprinting Control Regions (ICRs), and reinforces the differences in maintenance methylation of ICRs over non-imprinted regions. Consistent with nervous system abnormalities in the HSAN1E disorder and involvement of imprinted genes in normal development and neurogenesis, R1Dnmt1Y495C cells showed dysregulated pluripotency and neuron marker genes, and yielded more slender, shorter, and extensively branched neurons. We speculate that R1Dnmt1Y495C cells produce predominantly dimers containing mutant proteins, leading to a gradual and specific loss of ICR methylation during early human development.

Dynamic of centromere associated RNAs and the centromere loading of DNA repair proteins in growing oocytes.

Mammalian centromeres are generally composed of dispersed repeats and the satellites such as α-satellites in human and major/minor satellites in mouse. Transcription of centromeres by RNA polymerase II is evolutionary conserved and critical for kinetochore assembly. In addition, it has been found that the transcribed satellite RNAs can bind DNA repair proteins such as MRE11 and PRKDC, and excessively expressed satellite RNAs could induce genome instability and facilitate tumorigenesis. During the maturation of female oocyte, centromeres are critical for accurate segregation of homologous chromosomes and sister chromatids. However, the dynamics of oocyte centromere transcription and whether it associated with DNA repair proteins are unknown. In this study, we found the transcription of centromeres is active in growing oocytes but it is silenced when oocytes are fully grown. DNA repair proteins like Mlh1, Mre11 and Prkdc are found associated with the minor satellites and this association can be interfered by RNA polymerase II inhibitor α-amanitin. When the growing oocyte is in vitro matured, Mlh1/Mre11/Prkdc foci would release from centromeres to the ooplasm. If the oocytes are treated with Mre11 inhibitor Mirin, the meiosis resumption of growing oocytes with Mre11 foci can be suppressed. These data revealed the dynamic of centromeric transcription in oocytes and its potential association with DNA repair proteins, which provide clues about how oocytes maintain centromere stability and assemble kinetochores.

One–Two Quench: A Double Minor Merger Scenario

Abstract Using the N-body+Smoothed particle hydrodynamics code, ChaNGa, we identify two merger-driven processes—disk disruption and supermassive black hole (SMBH) feedback—which work together to quench L * galaxies for over 7 Gyr. Specifically, we examine the cessation of star formation in a simulated Milky Way (MW) analog, driven by an interaction with two minor satellites. Both interactions occur within ∼100 Myr of each other, and the satellites both have masses 5–20 times smaller than that of their MW-like host galaxy. Using the genetic modification process of Roth et al., we generate a set of four zoom-in, MW-mass galaxies all of which exhibit unique star formation histories due to small changes to their assembly histories. In two of these four cases, the galaxy is quenched by z = 1. Because these are controlled modifications, we are able to isolate the effects of two closely spaced minor merger events, the relative timing of which determines whether the MW-mass main galaxy quenches. This one–two punch works to: (1) fuel the SMBH at its peak accretion rate and (2) disrupt the cold, gaseous disk of the host galaxy. The end result is that feedback from the SMBH thoroughly and abruptly ends the star formation of the galaxy by z ≈ 1. We search for and find a similar quenching event in Romulus25, a hydrodynamical (25 Mpc)3 volume simulation, demonstrating that the mechanism is common enough to occur even in a small sample of MW-mass quenched galaxies at z = 0.

Distinct Regulation of the Expression of Satellite DNAs in the Beetle Tribolium castaneum.

In the flour beetle, Tribolium castaneum (peri)centromeric heterochromatin is mainly composed of a major satellite DNA TCAST1 interspersed with minor satellites. With the exception of heterochromatin, clustered satellite repeats are found dispersed within euchromatin. In order to uncover a possible satellite DNA function within the beetle genome, we analysed the expression of the major TCAST1 and a minor TCAST2 satellite during the development and upon heat stress. The results reveal that TCAST1 transcription was strongly induced at specific embryonic stages and upon heat stress, while TCAST2 transcription is stable during both processes. TCAST1 transcripts are processed preferentially into piRNAs during embryogenesis and into siRNAs during later development, contrary to TCAST2 transcripts, which are processed exclusively into piRNAs. In addition, increased TCAST1 expression upon heat stress is accompanied by the enrichment of the silent histone mark H3K9me3 on the major satellite, while the H3K9me3 level at TCAST2 remains unchanged. The transcription of the two satellites is proposed to be affected by the chromatin state: heterochromatin and euchromatin, which are assumed to be the prevalent sources of TCAST1 and TCAST2 transcripts, respectively. In addition, distinct regulation of the expression might be related to diverse roles that major and minor satellite RNAs play during the development and stress response.

New Method of Recording Sunspots and Planets

A new method for recording planets and searching for minor planets (asteroids), AISs, and satellites passing along the solar disk—an advanced method of Doppler tomography—has been developed. This method, due to its high sensitivity, will also allow one to detect exoplanets and specify elements of planetary orbits and the parameters of their stars. It can be used to determine the shape of stars and the distribution of surface brightness, as well as analyze the rotation of the star surface and its active regions (spots, flares, etc.). Finally, it will allow one to establish the shape of planets, AISs, and satellites passing along the star disk. It is based on analysis by high-resolution spectral devices of variations in the profiles of the emission and absorption lines of stars, broadened due to the rotation of stars or flows of emitting gases. For the use of high-resolution spectroscopies, new types of telescopes–spectrographs of record luminosity and a scheme of a mirror collimator–condenser are proposed. Possible manifestations of the Ritz effect in these measurements are considered.

Targeted DNA methylation in pericentromeres with genome editing-based artificial DNA methyltransferase.

To study the impact of epigenetic changes on biological functions, the ability to manipulate the epigenetic status of certain genomic regions artificially could be an indispensable technology. “Epigenome editing” techniques have gradually emerged that apply TALE or CRISPR/Cas9 technologies with various effector domains isolated from epigenetic code writers or erasers such as DNA methyltransferase, 5-methylcytosine oxidase, and histone modification enzymes. Here we demonstrate that a TALE recognizing a major satellite, consisting of a repeated sequence in pericentromeres, could be fused with the bacterial CpG methyltransferase, SssI. ChIP-qPCR assays demonstrated that the fusion protein TALMaj-SssI preferentially bound to major chromosomal satellites in cultured cell lines. Then, TALMaj-SssI was expressed in fertilized mouse oocytes with hypomethylated major satellites (10–20% CpG islands). Bisulfite sequencing revealed that the DNA methylation status was increased specifically in major satellites (50–60%), but not in minor satellites or other repeat elements, such as Intracisternal A-particle (IAP) or long interspersed nuclear elements-1 (Line1) when the expression level of TALMaj-SssI is optimized in the cell. At a microscopic level, distal ends of chromosomes at the first mitotic stage were dramatically highlighted by the mCherry-tagged methyl CpG binding domain of human MBD1 (mCherry-MBD-NLS). Moreover, targeted DNA methylation to major satellites did not interfere with kinetochore function during early embryonic cleavages. Co-injection of dCas9 fused with SssI and guide RNA (gRNA) recognizing major satellite sequences enabled increment of the DNA methylation in the satellites, but a few off-target effects were also observed in minor satellites and retrotransposons. Although CRISPR can be applied instead of the TALE system, technical improvements to reduce off-target effects are required. We have demonstrated a new method of introducing DNA methylation without the need of other binding partners using the CpG methyltransferase, SssI.

Obliquity evolution of the minor satellites of Pluto and Charon

New Horizons mission observations show that the small satellites Styx, Nix, Kerberos and Hydra, of the Pluto–Charon system, have not tidally spun-down to near synchronous spin states and have high obliquities with respect to their orbit about the Pluto–Charon binary (Weaver, 2016). We use a damped mass-spring model within an N-body simulation to study spin and obliquity evolution for single spinning non-round bodies in circumbinary orbit. Simulations with tidal dissipation alone do not show strong obliquity variations from tidally induced spin-orbit resonance crossing and this we attribute to the high satellite spin rates and low orbital eccentricities. However, a tidally evolving Styx exhibits intermittent obliquity variations and episodes of tumbling. During a previous epoch where Charon migrated away from Pluto, the minor satellites could have been trapped in orbital mean motion inclination resonances. An outward migrating Charon induces large variations in Nix and Styx’s obliquities. The cause is a commensurability between the mean motion resonance frequency and the spin precession rate of the spinning body. As the minor satellites are near mean motion resonances, this mechanism could have lifted the obliquities of all four minor satellites. The high obliquities need not be primordial if the minor satellites were at one time captured into mean motion resonances.

Combined exposure to protons and 56Fe leads to overexpression of Il13 and reactivation of repetitive elements in the mouse lung

Interest in deep space exploration underlines the needs to investigate the effects of exposure to combined sources of space radiation. The lung is a target organ for radiation, and exposure to protons and heavy ions as radiation sources may lead to the development of degenerative disease and cancer. In this study, we evaluated the pro-fibrotic and epigenetic effects of exposure to protons (150 MeV/nucleon, 0.1 Gy) and heavy iron ions (56Fe, 600 MeV/nucleon, 0.5 Gy) alone or in combination (protons on Day 1 and 56Fe on Day 2) in C57BL/6 male mice 4 weeks after irradiation. Exposure to 56Fe, proton or in combination, did not result in histopathological changes in the murine lung. At the same time, combined exposure to protons and 56Fe resulted in pronounced molecular alterations in comparison with either source of radiation alone. Specifically, we observed a substantial increase in the expression of cytokine Il13, loss of expression of DNA methyltransferase Dnmt1, and reactivation of LINE-1, SINE B1 retrotransposons, and major and minor satellites. Given the deleterious potential of the observed effects that may lead to development of chronic lung injury, pulmonary fibrosis, and cancer, future studies devoted to the investigation of the long-term effects of combined exposures to proton and heavy ions are clearly needed.

Analysis of the potential field and equilibrium points of irregular-shaped minor celestial bodies

The equilibrium points of the gravitational potential field of minor celestial bodies, including asteroids, comets, and irregular satellites of planets, are studied. In order to understand better the orbital dynamics of massless particles moving near celestial minor bodies and their internal structure, both internal and external equilibrium points of the potential field of the body are analyzed. In this paper, the location and stability of the equilibrium points of 23 minor celestial bodies are presented. In addition, the contour plots of the gravitational effective potential of these minor bodies are used to point out the differences between them. Furthermore, stability and topological classifications of equilibrium points are discussed, which clearly illustrate the topological structure near the equilibrium points and help to have an insight into the orbital dynamics around the irregular-shaped minor celestial bodies. The results obtained here show that there is at least one equilibrium point in the potential field of a minor celestial body, and the number of equilibrium points could be one, five, seven, and nine, which are all odd integers. It is found that for some irregular-shaped celestial bodies, there are more than four equilibrium points outside the bodies while for some others there are no external equilibrium points. If a celestial body has one equilibrium point inside the body, this one is more likely linearly stable.

Visualization of specific DNA sequences in living mouse embryonic stem cells with a programmable fluorescent CRISPR/Cas system

Labeling and tracing of specific sequences in living cells has been a major challenge in studying the spatiotemporal dynamics of native chromatin. Here we repurposed the prokaryotic CRISPR/Cas adaptive immunity system to specifically detect endogenous genomic loci in mouse embryonic stem cells. We constructed a catalytically inactive version of the Cas9 endonuclease, fused it with eGFP (dCas9-eGFP) and co-expressed small guide RNAs (gRNAs) to target pericentric, centric, and telomeric repeats, which are enriched in distinct nuclear structures. With major satellite specific gRNAs we obtained a characteristic chromocenter (CC) pattern, while gRNAs targeting minor satellites and telomeres highlighted smaller foci coinciding with centromere protein B (CENP-B) and telomeric repeat-binding factor 2 (TRF2), respectively. DNA sequence specific labeling by gRNA/dCas9-eGFP complexes was directly shown with 3D-fluorescent in situ hybridization (3D-FISH). Structured illumination microscopy (3D-SIM) of gRNA/dCas9-eGFP expressing cells revealed chromatin ultrastructures and demonstrated the potential of this approach for chromatin conformation studies by super resolution microscopy. This programmable dCas9 labeling system opens new perspectives to study functional nuclear architecture.

Evolution of the structure and composition of house mouse satellite DNA sequences in the subgenus Mus (Rodentia: Muridea): a cytogenomic approach

The composition and orientation of the house mouse satellite DNA sequences (minor, major, TLC) were investigated by a FISH and CO-FISH approach in 11 taxa belonging to three clades of the subgenus Mus. Using a phylogenetic framework, our results highlighted two distribution patterns. The TLC satellite, the most recently discovered satellite, was present in all clades but varied quantitatively among species. This distribution supported its appearance in the ancestor of the subgenus followed by independent evolution in species of each clade. In contrast, the minor and major satellites occurred in only two clades of the subgenus indicating the simultaneous and recent amplification of these sequences. In addition, although qualitative differences in the composition and orientation of the satellite sequences were observed among the taxa, none of the features studied were unique to the house mouse and could account for the extensive chromosomal plasticity evidenced in Mus musculus domesticus.

Characterizing the satellites of massive galaxies up to z ∼ 2: young populations to build the outskirts of nearby massive galaxies

The accretion of minor satellites is currently proposed as the most likely mechanism to explain the significant size evolution of the massive galaxies during the last ~10 Gyr. In this paper we investigate the rest-frame colors and the average stellar ages of satellites found around massive galaxies (Mstar 10^11Msun) since z~2. We find that the satellites have bluer colors than their central galaxies. When exploring the stellar ages of the galaxies, we find that the satellites have similar ages to the massive galaxies that host them at high redshifts, while at lower redshifts they are, on average, ~1.5 Gyr younger. If our satellite galaxies create the envelope of nearby massive galaxies, our results would be compatible with the idea that the outskirts of those galaxies are slightly younger, metal-poorer and with lower [alpha/Fe] abundance ratios than their inner regions.

The telocentric tandem repeat at the p-arm is not conserved in Mus musculus subspecies

Mouse chromosomes, with the exception of the Y chromosome, are telocentric. The telomere at the p-arm is separated from the centromere by the tL1 sequence and TLC tandem repeats. A previous report showed that the TLC array was also conserved in other strains of the subgenus Mus. These results suggest that the TLC arrays promote the stable evolutionary maintenance of a telocentric karyotype in the subgenus Mus. In this study, we investigated the degree of conservation of TLC arrays among a variety of wild-derived inbred strains, all of which are descendants of wild mice captured in several areas of the world. Genomic PCR analysis indicates that the sequential order of telomere-tL1 is highly conserved in all strains, whereas tL1-TLC is not. Next, Southern blot analysis of DNAs isolated from a panel of mouse subspecies showed both Mus musculus domesticus and Mus musculus castaneus subspecies possess TLC arrays. Unexpectedly, this repeat appears to be lost in almost all Mus musculus musculus and Mus musculus molossinus subspecies, which show a clear geographic divide. These results indicate that either other unknown sequences were replaced by the TLC repeat or almost all M. m. musculus and M. m. molossinus subspecies do not have any sequence between the telomere and minor satellites. Our observation suggests that the TLC array might be evolutionarily unstable and not essential for murine chromosomal conformation. This is the first example of the subspecies-specific large genome alterations in mice.

3D-FISH analysis of embryonic nuclei in mouse highlights several abrupt changes of nuclear organization during preimplantation development

BackgroundEmbryonic development proceeds through finely tuned reprogramming of the parental genomes to form a totipotent embryo. Cells within this embryo will then differentiate and give rise to all the tissues of a new individual. Early embryonic development thus offers a particularly interesting system in which to analyze functional nuclear organization. When the organization of higher-order chromatin structures, such as pericentromeric heterochromatin, was first analyzed in mouse embryos, specific nuclear rearrangements were observed that correlated with embryonic genome activation at the 2-cell stage. However, most existing analyses have been conducted by visual observation of fluorescent images, in two dimensions or on z-stack sections/projections, but only rarely in three dimensions (3D).ResultsIn the present study, we used DNA fluorescent in situ hybridization (FISH) to localize centromeric (minor satellites), pericentromeric (major satellites), and telomeric genomic sequences throughout the preimplantation period in naturally fertilized mouse embryos (from the 1-cell to blastocyst stage). Their distribution was then analyzed in 3D on confocal image stacks, focusing on the nucleolar precursor bodies and nucleoli known to evolve rapidly throughout the first developmental stages. We used computational imaging to quantify various nuclear parameters in the 3D-FISH images, to analyze the organization of compartments of interest, and to measure physical distances between these compartments.ConclusionsThe results highlight differences in nuclear organization between the two parental inherited genomes at the 1-cell stage, i.e. just after fertilization. We also found that the reprogramming of the embryonic genome, which starts at the 2-cell stage, undergoes other remarkable changes during preimplantation development, particularly at the 4-cell stage.

Satellites of massive galaxies: the infalling pieces of the puzzle

AbstractAccretion of minor satellites has been postulated as the most likely mechanism to explain the significant size evolution of massive galaxies over cosmic time. A direct way of probing this scenario is to measure the frequency of satellites around massive galaxies at different redshifts. Here we present our study of satellites around massive galaxies (Mstar ~ 1011 M⊙) up to z ~ 2. We find (Fig. 1) that the fraction of massive galaxies with satellites down to 1:10 mass ratio is ~15% (~30% down to 1:100), not varying with redshift (Mármol-Queraltó et al., (2012)). We also find that our satellites are younger than their central galaxies at low z (Mármol-Queraltó et al., 2013). Then, if minor merging is acting to form massive galaxies, their ourtskirts should be younger than their cores. The challenge to find this age gradient in nearby massive galaxies is opened.

Satellites around massive galaxies since z∼ 2

Accretion of minor satellites has been postulated as the most likely mechanism to explain the significant size evolution of the massive galaxies over cosmic time. Using a sample of 629 massive (Mstar~10^11 Msun) galaxies from the near-infrared Palomar/DEEP-2 survey, we explore which fraction of these objects has satellites with 0.01 Msat < Mcentral < 1 (1:100) up to z=1 and which fraction has satellites with 0.1 Msat < Mcentral < 1 (1:10) up to z=2 within a projected radial distance of 100 kpc. We find that the fraction of massive galaxies with satellites, after the background correction, remains basically constant and close to ~30% for satellites with a mass ratio down to 1:100 up to z=1, and ~15% for satellites with a 1:10 mass ratio up to z=2. The family of spheroid-like massive galaxies presents a 2-3 times larger fraction of objects with satellites than the group of disk-like massive galaxies. A crude estimation of the number of 1:3 mergers a massive spheroid-like galaxy experiences since z~2 is around 2. For a disk-like galaxy this number decreases to ~1.

Disc formation and the origin of clumpy galaxies at high redshift

Abstract Observations of high-redshift galaxies have revealed a multitude of large clumpy rapidly star-forming galaxies. Their formation scenario and their link to present-day spirals are still unknown. In this Letter, we perform adaptive mesh refinement simulations of disc formation in a cosmological context that are unrivalled in terms of mass and spatial resolution. We find that the so-called ‘chain-galaxies’ and ‘clump-clusters’ are a natural outcome of early epochs of enhanced gas accretion from cold dense streams as well as tidally and ram-pressured stripped material from minor mergers and satellites. Through interaction with the hot halo gas, this freshly accreted cold gas settles into a large disc-like system, not necessarily aligned to an older stellar component, that undergoes fragmentation and subsequent star formation, forming large clumps in the mass range 107–109 M⊙. Galaxy formation is a complex process at this important epoch when most of the central baryons are being acquired through a range of different mechanisms – we highlight that a rapid mass loading epoch is required to fuel the fragmentation taking place in the massive arms in the outskirts of extended discs, an accretion mode that occurs naturally in the hierarchical assembly process at early epochs.

Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet

The importance of epigenetic changes in etiology and pathogenesis of disease has been increasingly recognized. However, the role of epigenetic alterations in the genesis of hepatic steatosis and cause of individual susceptibilities to this pathological state are largely unknown. Male inbred C57BL/6J and DBA/2J mice were fed a lipogenic methyl-deficient diet (MDD) that causes liver injury similar to human non-alcoholic steatohepatitis (NASH) for 6, 12, or 18 weeks, and the status of global and repetitive elements cytosine methylation, histone modifications, and expression of proteins responsible for those epigenetic modifications in livers was determined. The development of hepatic steatosis in inbred C57BL/6J and DBA/2J mice was accompanied by prominent epigenetic abnormalities. This was evidenced by pronounced loss of genomic and repetitive sequences cytosine methylation, especially at major and minor satellites, accompanied by increased levels of repeat-associated transcripts, aberrant histone modifications, and alterations in expression of the maintenance DNA methyltransferase 1 (DNMT1) and de novo DNMT3A proteins in the livers of both mouse strains. However, the DBA/2J mice, which were characterized by an initially lower degree of methylation of repetitive elements and lower extent of histone H3 lysine 9 (H3K9) and H3 lysine 27 (H3K27) trimethylation in the normal livers, as compared to those in the C57BL/6J mice, developed more prominent NASH-specific pathomorphological changes. These results mechanistically link epigenetic alterations to the pathogenesis of hepatic steatosis and strongly suggest that differences in the cellular epigenetic status may be a predetermining factor to individual susceptibilities to hepatic steatosis.