Endoscopic Aortic Valve Replacement: Initial Outcomes of Isolated and Concomitant Surgery.

BACKGROUND: The applicability of totally endoscopic surgical aortic valve replacement (AVR) in multivalve operations is unknown. This study describes an approach and perioperative outcomes of totally endoscopic isolated and concomitant AVR using various valve types. METHODS: A total of 216 patients (114 male; mean age, 71.3 ± 11.3 years) underwent totally endoscopic AVR from May 2017 to October 2022 in a tertiary care center. The 3-port technique was used: a 3- to 4-cm main port without rib spreading, a 10-mm 3-dimensional endoscopic port, and a 5-mm left-hand port with femoral cannulations. Sutures were hand tied with a knot pusher. Descriptive analyses compared perioperative outcomes between patients with or without concomitant procedures. RESULTS: Of 216 patients, concomitant surgery was performed in 33 (15.2%) patients. Of the 33, 21 (63.6%) had a concomitant mitral procedure. A stented bioprosthesis was implanted in 165 (76.3%) patients, a mechanical valve in 22 (10.2%) patients, and a rapid deployment or sutureless valve in 29 (13.4%) patients. Median operation time and aortic cross-clamp time were 175 minutes (interquartile range; 150-194 minutes) and 78 minutes (interquartile range; 67-92 minutes) for isolated AVR, respectively. Thirty-day mortality occurred in 1 patient (0.5%). Two patients (0.9%) had conversion to sternotomy. Major neurologic events occurred in 3 patients (1.4%). The major adverse event rate was similar between patients with or without concomitant procedures. CONCLUSIONS: Endoscopic AVR can safely address concomitant valve diseases.

Midterm results after seamless patch mitral reconstruction.

Objectives: Some pathologies, including infective endocarditis or sclerotic changes of the mitral leaflet, make the conventional mitral valve repair challenging. Our previously described technique for reconstruction with a seamless pericardial patch makes the repair feasible in some of such difficult pathologies. However, the extent of mitral leaflet segments that could be safely repaired using this technique remains unknown. We investigated the association between the midterm outcome and the extent of mitral leaflet segments replaced by a pericardial patch. Methods: From January 2009 to January 2022, patients who underwent mitral valve repair with the seamless 1-patch reconstruction technique were included. The glutaraldehyde-treated pericardium was trimmed and anchored at the papillary muscle. The edge was sewn to the leaflet and the annulus. Results: A total of 49 patients (aged 60 ± 15 years) underwent mitral valve repair with this technique. The totally endoscopic approach was used in 27 patients (55%). No patient's repair was converted to valve replacement. No operative mortality or disabling stroke was observed during the early postoperative period. In the midterm follow-up, redo surgery was required in 9 patients (18%). Freedom from mitral valve reintervention rates at 1, 5, and 10 years were 84%, 82%, and 82% for all patients, respectively. Freedom from reoperation at 5 years was 100%, 92%, and 46% for commissural lesion, 1- to 2-segment involvement, and 3-segment involvement, respectively. There was a significant difference among the 3 groups with regard to mitral valve reoperation rate (P = .002). Conclusions: Mitral valve seamless patch reconstruction provides excellent midterm results if applied to commissural lesions or lesions involving up to 2 segments.

Transcriptome and Methylome Profiling in Rat Skeletal Muscle: Impact of Post-Weaning Protein Restriction.

Skeletal muscle is programmable, and early-life nutritional stimuli may form epigenetic memory in the skeletal muscle, thus impacting adult muscle function, aging, and longevity. In the present study, we designed a one-month protein restriction model using post-weaning rats, followed by a two-month rebound feeding, to investigate how early-life protein restriction affects overall body growth and muscle development and whether these influences could be corrected by rebound feeding. We observed comprehensive alterations immediately after protein restriction, including retarded growth, altered biochemical indices, and disturbed hormone secretion. Transcriptome profiling of the gastrocnemius muscle followed by gene ontology analyses revealed that "myogenic differentiation functions" were upregulated, while "protein catabolism" was downregulated as a compensatory mechanism, with enhanced endoplasmic reticulum stress and undesired apoptosis. Furthermore, methylome profiling of the gastrocnemius muscle showed that protein restriction altered the methylation of apoptotic and hormone secretion-related genes. Although most of the alterations were reversed after rebound feeding, 17 genes, most of which play roles during muscle development, remained altered at the transcriptional level. In summary, early-life protein restriction may undermine muscle function in the long term and affect skeletal muscle development at the both transcriptional and methylation levels, which may hazard future muscle health.

Compulsory drainage of inferior vena cava to obtain bloodless field in minimally invasive mitral valve surgery.

Gaining bloodless field in minimally invasive mitral valve surgery is crucial for a successful surgery. We here demonstrate a simple method to obtain bloodless field in minimally invasive mitral valve surgery with only single venous cannula through the femoral vein. A dual-stage venous cannula is inserted through the femoral vein, with its tip located deep in superior vena cava. After establishing full flow, the inferior vena cava (IVC) was snared. Returning blood from the IVC was blocked at the snare, and drained through the side holes at the midportion of the cannula. This technique collapsed the right atrium, and made the left atrium almost bloodless. Pressures of the femoral vein measured in 28 patients were 9.5 ± 4.1 mmHg before bypass, 6.8 ± 4.8 mmHg before snaring IVC, and 7.2 ± 4.8 mmHg after snaring. By blocking returning blood from the lower body, venous congestion of the lower body did not occur.

Shoot base responds to root-applied glutathione and functions as a critical region to inhibit cadmium translocation from the roots to shoots in oilseed rape (Brassica napus).

Glutathione (GSH) is a tripeptide involved in controlling heavy metal movement in plants. Our previous study showed that GSH, when site-specifically applied to plant roots, inhibits Cd translocation from the roots to shoots in hydroponically cultured oilseed rape (Brassica napus) plants. A factor that led to this inhibitory effect was the activation of Cd efflux from root cells. To further investigate the molecular mechanism triggered by root-applied GSH, Cd movement was non-invasively monitored using a positron-emitting tracer imaging system. The Cd absorption and efflux process in the roots were visualized successfully. The effects of GSH on Cd efflux from root cells were estimated by analyzing imaging data. Reanalysis of image data suggested that GSH applied to roots, at the shoot base, activated Cd return. Cutting the shoot base significantly inhibited Cd efflux from root cells. These experimental results demonstrate that the shoot base plays an important role in distributing Cd throughout the plant body. Furthermore, microarray analysis revealed that about 400 genes in the roots responded to root-applied GSH. Among these, there were genes for transporter proteins related to heavy metal movement in plants and proteins involved in the structure modification of cell walls.

Role for phagocytosis in the prevention of neoplastic transformation in Drosophila.

Immunity is considered to be involved in the prevention of cancer. Although both humoral and cellular immune reactions may participate, underlying mechanisms have yet to be clarified. The present study was conducted to clarify this issue using a Drosophila model, in which neoplastic transformation was induced through the simultaneous inhibition of cell-cycle checkpoints and apoptosis. We first determined the location of hemocytes, blood cells of Drosophila playing a role of immune cells, in neoplasia-induced and normal larvae, but there was no significant difference between the two groups. When gene expression pattern in larval hemocytes was determined, the expression of immunity-related genes including those necessary for phagocytosis was reduced in the neoplasia model. We then asked the involvement of phagocytosis in the prevention of neoplasia examining animals where the expression of engulfment receptors instead of apoptosis was retarded. We found that the inhibition of engulfment receptor expression augmented the occurrence of neoplasia induced by a defect in cell-cycle checkpoints. This suggested a role for phagocytosis in the prevention of neoplastic transformation in Drosophila.

Dietary Intake of Carotenoid-Rich Vegetables Reduces Visceral Adiposity in Obese Japanese men-A Randomized, Double-Blind Trial.

Metabolic syndrome, whose main diagnostic component is obesity, is a risk factor for lifestyle-related diseases, type 2 diabetes, and cardiovascular disease. Diet is known to affect the prevalence of metabolic syndrome. However, the effect of diet on metabolic syndrome in Japanese subjects has not been thoroughly explored. In the present study, we investigated the effect of carotenoid-rich vegetables, particularly lycopene- and lutein-rich vegetables, on the metabolic syndrome in obese Japanese men. We conducted an 8-week long randomized, double-blinded, controlled clinical trial in which, 28 middle-aged (40 ≤ age < 65) Japanese men with high body mass index (BMI ≥ 25) were randomized into four dietary groups: high lycopene + high lutein (HLyHLu), high lycopene + low lutein (HLyLLu), low lycopene + high lutein (LLyHLu), and low lycopene + low lutein (LLyLLu). Our results showed that daily beverage-intake increased the plasma levels of carotenoids without adverse effects, and the visceral fat level was significantly decreased in all the groups. The waist circumference was significantly decreased only in the HLyLLu group, whereas the CoQ10 oxidation rate was decreased in all the groups. The gene expression profiles of whole blood samples before and after ingestion differed only in the LLyLLu group, indicating the effect of carotenoids on gene expression profile. In conclusion, our results suggest that dietary uptake of carotenoid-rich vegetables increases their concentration in blood and reduces the intra-abdominal visceral fat.

DMHF (2,5-dimethyl-4-hydroxy-3(2H)-furanone), a volatile food component generated by the Maillard reaction, promotes appetite and changes gene expression in the rat brain through inhalation.

Inhalation of odors can affect physiological parameter and change gene expression-related specific function. 2,5-Dimethyl-4-hydroxy-3(2H)-furanone (DMHF) is one of the major odor compounds generated by the Maillard reaction. We previously reported that the inhalation of DMHF decreased systolic blood pressure via the autonomic nervous system in rats. The autonomic nervous system is also closely related to appetite regulation. The present study investigated the effects of DMHF on dietary intake and gene expression. The inhalation of DMHF increased the dietary intake of rats during the feeding period. However, body weight did not change after 6 weeks feeding. A DNA microarray analysis showed that DMHF altered gene expression associated with feeding behavior and neurotransmission in the rat brain. DMHF inhalation promotes appetite and changes gene expression in rats. Furthermore, phenotypic changes may regulate neurotransmission and appetite at the mRNA level in addition to controlling the autonomic nervous system. PRACTICAL APPLICATION: DMHF is an important flavor component in the food industry. In this study, we first observed that the inhalation of DMHF promotes appetite. This finding is directly connected with the industrial application.

A maple syrup extract alleviates liver injury in type 2 diabetic model mice.

A recent study showed that 54% of type 2 diabetes (T2D) patients have nonalcoholic fatty liver disease, which is a risk factor for aggravation diabetic symptoms. Previous studies suggested components in maple syrup alleviated liver injury and found polyphenols as food components to improve the symptoms and complications of diabetes. Therefore, we hypothesized that a polyphenol fraction in maple syrup improves the symptoms and complications of diabetes. To address the hypothesis, we investigated the effects of a polyphenol-rich maple syrup extract (MSE) on a T2D model mice. KK-Ay mice were fed a normal or 0.1% MSE-supplemented diet for 43 days. The results showed that the levels of serum alanine aminotransferase and aspartate aminotransferase were significantly reduced in mice that ingested MSE. Hepatic genes related to lipogenesis and lipolysis were down- and upregulated, respectively, in mice that ingested MSE. These results suggest that MSE intake alleviates liver injury and suppresses lipid accumulation in the livers of T2D mice.

Identification of Radiation-Dose-Dependent Expressive Genes in Individuals Exposed to External Ionizing Radiation.

For victims of radiological accidents, rapid dose estimation and damage prediction are essential. Administering the gold-standard biodosimetry chromosome aberration assay requires highly skilled individuals and several days of labor; consequently, rapid turnaround is an important concern. Identification of new dose estimation markers and damage-predicting in vivo molecules to replace the chromosome aberration assay is crucial to improving the delivery time of medical treatment. Here, we investigated the applicability of mRNA levels using a mouse model. Female C57BL/6J mice were X-ray irradiated at various doses, and a DNA microarray was then performed to identify differentially expressed mRNAs in whole blood. The microarray analysis identified 14 radioresponsive mRNAs with more than fourfold differences by pattern matching in the expression at 24 h postirradiation. In particular, mRNA expression of Slfn4, Itgb5, Smim3, Tmem40, Litaf, Gp1bb and Cxx1c was significantly increased in a radiation-dose-dependent manner, as validated by reverse transcription quantitative polymerase chain reaction. We also performed an analysis using the cBioPortal for Cancer Genomics and found that the overall survival of ovarian adenocarcinoma patients with alterations in Smim3 and that of thymoma patients with alterations in Cxx1c had a worse prognosis than patients without these alterations. These findings suggest that the expression of several genes in whole blood was a sensitive and specific biomarker of radiation exposure and can be used as a rapid and reliable prospective molecular biomarker in radiological emergencies.

Ribosome Reconstruction during Recovery from High-Hydrostatic-Pressure-Induced Injury in Bacillus subtilis.

Vegetative cells of Bacillus subtilis can recover from injury after high-hydrostatic-pressure (HHP) treatment at 250 MPa. DNA microarray analysis revealed that substantial numbers of ribosomal genes and translation-related genes (e.g., translation initiation factors) were upregulated during the growth arrest phase after HHP treatment. The transcript levels of cold shock-responsive genes, whose products play key roles in efficient translation, and heat shock-responsive genes, whose products mediate correct protein folding or degrade misfolded proteins, were also upregulated. In contrast, the transcript level of hpf, whose product (Hpf) is involved in ribosome inactivation through the dimerization of 70S ribosomes, was downregulated during the growth arrest phase. Sucrose density gradient sedimentation analysis revealed that ribosomes were dissociated in a pressure-dependent manner and then reconstructed. We also found that cell growth after HHP-induced injury was apparently inhibited by the addition of Mn2+ or Zn2+ to the recovery medium. Ribosome reconstruction in the HHP-injured cells was also significantly delayed in the presence of Mn2+ or Zn2+ Moreover, Zn2+, but not Mn2+, promoted dimer formation of 70S ribosomes in the HHP-injured cells. Disruption of the hpf gene suppressed the Zn2+-dependent accumulation of ribosome dimers, partially relieving the inhibitory effect of Zn2+ on the growth recovery of HHP-treated cells. In contrast, it was likely that Mn2+ prevented ribosome reconstruction without stimulating ribosome dimerization. Our results suggested that both Mn2+ and Zn2+ can prevent ribosome reconstruction, thereby delaying the growth recovery of HHP-injured B. subtilis cells.IMPORTANCE HHP treatment is used as a nonthermal processing technology in the food industry to inactivate bacteria while retaining high quality of foods under suppressed chemical reactions. However, some populations of bacterial cells may survive the inactivation. Although the survivors are in a transient nongrowing state due to HHP-induced injury, they can recover from the injury and then start growing, depending on the postprocessing conditions. The recovery process in terms of cellular components after the injury remains unclear. Transcriptome analysis using vegetative cells of Bacillus subtilis revealed that the translational machinery can preferentially be reconstructed after HHP treatment. We found that both Mn2+ and Zn2+ prolonged the growth-arrested stage of HHP-injured cells by delaying ribosome reconstruction. It is likely that ribosome reconstruction is crucial for the recovery of growth ability in HHP-injured cells. This study provides further understanding of the recovery process in HHP-injured B. subtilis cells.

Foliar-applied glutathione activates zinc transport from roots to shoots in oilseed rape.

Glutathione is a tripeptide involved in diverse aspects of plant metabolism. We investigated how the reduced form of glutathione, GSH, applied site-specifically to plants, affects zinc (Zn) distribution and behavior in oilseed rape plants (Brassica napus) cultured hydroponically. Foliar-applied GSH significantly increased the Zn content in shoots and the root-to-shoot Zn translocation ratio; furthermore, this treatment raised the Zn concentration in the cytosol of root cells and substantially enhanced Zn xylem loading. Notably, microarray analysis revealed that the gene encoding pectin methylesterase was upregulated in roots following foliar GSH treatment. We conclude that certain physiological signals triggered in response to foliar-applied GSH were transported via sieve tubes and functioned in root cells, which, in turn, increased Zn availability in roots by releasing Zn from their cell wall. Consequently, root-to-shoot translocation of Zn was activated and Zn accumulation in the shoot was markedly increased.

The Anti-Arthritis Effect of Olive-Derived Maslinic Acid in Mice is Due to its Promotion of Tissue Formation and its Anti-Inflammatory Effects.

SCOPE: A previous study demonstrated that intake of olive pomace extract containing maslinic acid (MA), a triterpene, effectively prevents and alleviates arthritis in animals and humans. Here, the molecular mechanisms involved in the anti-arthritis effect of MA have been elucidated by determining gene expression changes induced by olive-derived MA intake in collagen antibody-induced arthritis (CAIA) mice. METHODS AND RESULTS: Mice are divided into the untreated (CT), CAIA (CA), and CAIA administered MA (CA + MA) groups. The CA + MA mice are fed MA at a daily dose of 200 mg kg-1 of body weight from day 1. CAIA is then induced on day 8 and evaluated on day 12. Arthritis symptoms are alleviated, and the gene expression of inflammatory cytokines is reduced in the CA + MA group compared with the CA group. A DNA microarray analysis of synovial membranes reveals that MA alters the expression levels of genes related to inflammation, including glucocorticoid responses, immune responses, and the extracellular matrix. CONCLUSIONS: The preventive effect of MA on arthritis is attributable to the promotion of tissue formation as well as suppression of inflammation in the synovium via inactivation of Toll-like receptor signaling and downregulation of leukotrienes through the glucocorticoid receptor.

Dose-Dependent Increase of Nrf2 Target Gene Expression in Mice Exposed to Ionizing Radiation.

Nuclear factor-erythroid-2-related factor 2 transcription factor (Nrf2) is activated by reactive oxygen species (ROS) and binds to antioxidant response elements in the promoter regions of its target genes involved in redox regulation and antioxidative functions. In this study, we elucidated the relationship between radiation dose and the expression response of Nrf2 target genes involved in oxidative stress, such as heme oxygenase 1, ferritin heavy polypeptide 1 ( Fth1), NADPH dehydrogenase quinone 1, glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase modifier subunit, glutathione reductase ( Gsr) and thioredoxin reductase 1 genes, in peripheral blood from X-ray irradiated mice. Whole-body radiation doses ranged from 0.5 to 3 Gy, and gene expressions were analyzed using reverse transcription quantitative polymerase chain reaction. A significant relationship was observed only for one gene: a statistically significant positive correlation between radiation dose and Fth1 mRNA expression was detected. However, Fth1 did not show any correlations with the biological damages induced by radiation tested in this study. Furthermore, while Gsr expression was significantly associated with spleen weight loss, splenic cell number reduction and bone marrow cell death apoptosis, no significant correlation was observed between Gsr expression and radiation dose. Together these results indicate that Nrf2 target gene expression is closely related to radiation dose and its level may reflect biological damages induced by ionizing radiation. These findings suggest the possibility for application of these target genes as a bio-dosimeter and/or damage marker in individuals exposed to ionizing radiation.

The Gα12/13-coupled receptor LPA4 limits proper adipose tissue expansion and remodeling in diet-induced obesity.

White adipose tissue (WAT) can dynamically expand and remodel through adipocyte hypertrophy and hyperplasia. The relative contribution of these 2 mechanisms to WAT expansion is a critical determinant of WAT function and dysfunction in obesity. However, little is known about the signaling systems that determine the mechanisms of WAT expansion. Here, we show that the GPCR LPA4 selectively activates Gα12/13 proteins in adipocytes and limits continuous remodeling and healthy expansion of WAT. LPA4-KO mice showed enhanced expression of mitochondrial and adipogenesis genes and reduced levels of inhibitory phosphorylation of PPARγ in WAT, along with increased production of adiponectin. Furthermore, LPA4-KO mice showed metabolically healthy obese phenotypes in a diet-induced obesity model, with continuous WAT expansion, as well as protection from WAT inflammation, hepatosteatosis, and insulin resistance. These findings unravel a potentially new signaling system that underlies WAT plasticity and expandability, providing a promising therapeutic approach for obesity-related metabolic disorders.

DNMTs and SETDB1 function as co-repressors in MAX-mediated repression of germ cell-related genes in mouse embryonic stem cells.

In embryonic stem cells (ESCs), the expression of development-related genes, including germ cell-related genes, is globally repressed. The transcription factor MAX represses germ cell-related gene expression in ESCs via PCGF6-polycomb repressive complex 1 (PRC1), which consists of several epigenetic factors. However, we predicted that MAX represses germ cell-related gene expression through several additional mechanisms because PCGF6-PRC1 regulates the expression of only a subset of genes repressed by MAX. Here, we report that MAX associated with DNA methyltransferases (DNMTs) and the histone methyltransferase SETDB1 cooperatively control germ cell-related gene expression in ESCs. Both DNA methylation and histone H3 lysine 9 tri-methylation of the promoter regions of several germ cell-related genes were not affected by knockout of the PRC1 components, indicating that the MAX-DNMT and MAX-SETDB1 pathways are independent of the PCGF6-PRC1 pathway. Our findings provide insights into our understanding of MAX-based repressive mechanisms of germ cell-related genes in ESCs.

Placenta Specific 8 Suppresses IL-18 Production through Regulation of Autophagy and Is Associated with Adult Still Disease.

Adult Still disease (ASD) is a systemic disorder of unknown etiology characterized by high spiking fever, rash, and arthritis. The purpose of this study was to identify genes specifically associated with the active phase of the disease. In this study, we have reported that placenta specific 8 (PLAC8) was a newly specific gene involved in ASD. DNA microarray and validation analysis using human monocytes revealed that the expression of PLAC8 was significantly higher in active-ASD patients than in inactive-ASD patients and healthy controls. In ASD, PLAC8 expression level correlated with serum levels of CRP, ferritin, IL-1ß, and IL-18. Stimulation of monocytes with LPS results in PLAC8 upregulation. LPS or nigericin stimulation of PLAC8-overexpressing human monocytic cell line (THP-1), but not mock THP-1 cells, was associated with a significant decrease in IL-1ß and IL-18 production. PLAC8 overexpression in THP-1 cells was associated with enhanced autophagy and suppression of IL-1ß and IL-18 production. Therefore, we found that PLAC8 was upregulated in activated monocytes, as was IL-1ß and IL-18. The upregulated PLAC8 acts on the synthesis of inactive precursors of IL-1ß and IL-18 and seemed to suppress the production of IL-1ß and IL-18 by negative feedback through enhanced autophagy, resulting in the suppression of ASD. The results highlight the role of PLAC8 in the pathogenesis of ASD and suggest its potential suitability as an activity marker and therapeutic target in ASD.

Hepatic fatty acid biosynthesis in KK-Ay mice is modulated by administration of persimmon peel extract: A DNA microarray study.

SCOPE: Previously, we showed that the intake of a persimmon peel (PP) extract altered hepatic gene expression associated with the insulin signaling pathway and enhanced tyrosine phosphorylation of insulin receptors in nonobese type 2 diabetic Goto-Kakizaki rats. Our objective was to evaluate the effect of fat-soluble PP extract on obese type 2 diabetic KK-Ay mice with insulin resistance. METHODS AND RESULTS: KK-Ay mice were fed a diet mixed with 0.1% of the extract for 8 weeks. The total ketone body levels in the plasma of PP extract-fed mice were significantly lower than those in the normal diet-fed mice. Hepatic nonesterified palmitic acid content was higher in the PP extract-fed mice than in normal diet-fed mice. The hepatic gene expression profiles of the treated mice indicated upregulation of fatty acid synthesis and downregulation of inflammation-associated genes, predicting SREBP-1c and PPARγ activation. CONCLUSION: These results suggest that the PP extract enhances hepatic fatty acid synthesis via SREBP-1c and PPARγ, as well as anti-inflammatory activity in KK-Ay mice.

Oral Administration of Edible Seaweed Undaria Pinnatifida (Wakame) Modifies Glucose and Lipid Metabolism in Rats: A DNA Microarray Analysis.

SCOPE: Wakame is an edible seaweed that is a common constituent in the Japanese diet. Previous studies showed that wakame consumption is associated with the prevention of metabolic syndrome, but the molecular mechanisms underlying the protective effects are poorly understood. METHODS AND RESULTS: To determine if the expression of hepatic genes is affected by ingestion of the brown seaweed Undaria pinnatifida (wakame), rats were fed a diet containing 0, 0.1, or 1.0 g per 100 g dried wakame powder for 28 days. Administration of 1% wakame significantly decreased serum total cholesterol levels. Hepatic gene expression was investigated using DNA microarray analysis, and the results showed that wakame suppresses the lipogenic pathway by downregulating SREBF-1. Moreover, bile acid biosynthesis and gluconeogenesis were promoted by upregulation of the PPAR signaling pathway, which leads to a reduction in the accumulation of cholesterol and promotion of ß-oxidation. CONCLUSIONS: These results suggest that wakame ingestion affects glucose and lipid metabolism by altering the expression of SREBF-1 and PPAR signal-related genes.

Combined Loss of JMJD1A and JMJD1B Reveals Critical Roles for H3K9 Demethylation in the Maintenance of Embryonic Stem Cells and Early Embryogenesis.

Histone H3 lysine 9 (H3K9) methylation is unevenly distributed in mammalian chromosomes. However, the molecular mechanism controlling the uneven distribution and its biological significance remain to be elucidated. Here, we show that JMJD1A and JMJD1B preferentially target H3K9 demethylation of gene-dense regions of chromosomes, thereby establishing an H3K9 hypomethylation state in euchromatin. JMJD1A/JMJD1B-deficient embryos died soon after implantation accompanying epiblast cell death. Furthermore, combined loss of JMJD1A and JMJD1B caused perturbed expression of metabolic genes and rapid cell death in embryonic stem cells (ESCs). These results indicate that JMJD1A/JMJD1B-meditated H3K9 demethylation has critical roles for early embryogenesis and ESC maintenance. Finally, genetic rescue experiments clarified that H3K9 overmethylation by G9A was the cause of the cell death and perturbed gene expression of JMJD1A/JMJD1B-depleted ESCs. We summarized that JMJD1A and JMJD1B, in combination, ensure early embryogenesis and ESC viability by establishing the correct H3K9 methylated epigenome.