Inhibition of fatty acid oxidation enables heart regeneration in adult mice.

Postnatal maturation of cardiomyocytes is characterized by a metabolic switch from glycolysis to fatty acid oxidation, chromatin reconfiguration and exit from the cell cycle, instating a barrier for adult heart regeneration1,2. Here, to explore whether metabolic reprogramming can overcome this barrier and enable heart regeneration, we abrogate fatty acid oxidation in cardiomyocytes by inactivation of Cpt1b. We find that disablement of fatty acid oxidation in cardiomyocytes improves resistance to hypoxia and stimulates cardiomyocyte proliferation, allowing heart regeneration after ischaemia-reperfusion injury. Metabolic studies reveal profound changes in energy metabolism and accumulation of α-ketoglutarate in Cpt1b-mutant cardiomyocytes, leading to activation of the α-ketoglutarate-dependent lysine demethylase KDM5 (ref. 3). Activated KDM5 demethylates broad H3K4me3 domains in genes that drive cardiomyocyte maturation, lowering their transcription levels and shifting cardiomyocytes into a less mature state, thereby promoting proliferation. We conclude that metabolic maturation shapes the epigenetic landscape of cardiomyocytes, creating a roadblock for further cell divisions. Reversal of this process allows repair of damaged hearts.

ADAR1 Prevents Autoinflammatory Processes in the Heart Mediated by IRF7.

BACKGROUND: ADAR1 (adenosine deaminase acting on RNA-1)-mediated adenosine to inosine (A-to-I) RNA editing plays an essential role for distinguishing endogenous from exogenous RNAs, preventing autoinflammatory ADAR1 also regulates cellular processes by recoding specific mRNAs, thereby altering protein functions, but may also act in an editing-independent manner. The specific role of ADAR1 in cardiomyocytes and its mode of action in the heart is not fully understood. To determine the role of ADAR1 in the heart, we used different mutant mouse strains, which allows to distinguish immunogenic, editing-dependent, and editing-independent functions of ADAR1. METHODS: Different Adar1-mutant mouse strains were employed for gene deletion or specific inactivation of ADAR1 enzymatic activity in cardiomyocytes, either alone or in combination with Ifih1 (interferon induced with helicase C domain 1) or Irf7 (interferon regulatory factor 7) gene inactivation. Mutant mice were investigated by immunofluorescence, Western blot, RNAseq, proteomics, and functional MRI analysis. RESULTS: Inactivation of Adar1 in cardiomyocytes resulted in late-onset autoinflammatory myocarditis progressing into dilated cardiomyopathy and heart failure at 6 months of age. Adar1 depletion activated interferon signaling genes but not NFκB (nuclear factor kappa B) signaling or apoptosis and reduced cardiac hypertrophy during pressure overload via induction of Irf7. Additional inactivation of the cytosolic RNA sensor MDA5 (melanoma differentiation-associated gene 5; encoded by the Ifih1 gene) in Adar1 mutant mice prevented activation of interferon signaling gene and delayed heart failure but did not prevent lethality after 8.5 months. In contrast, compound mutants only expressing catalytically inactive ADAR1 in an Ifih1-mutant background were completely normal. Inactivation of Irf7 attenuated the phenotype of Adar1-deficient cardiomyocytes to a similar extent as Ifih1 depletion, identifying IRF7 as the main mediator of autoinflammatory responses caused by the absence of ADAR1 in cardiomyocytes. CONCLUSIONS: Enzymatically active ADAR1 prevents IRF7-mediated autoinflammatory reactions in the heart triggered by endogenous nonedited RNAs. In addition to RNA editing, ADAR1 also serves editing-independent roles in the heart required for long-term cardiac function and survival.

Epigenetic Regulation by Suv4-20h1 in Cardiopulmonary Progenitor Cells Is Required to Prevent Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease.

BACKGROUND: The pathogenesis of life-threatening cardiopulmonary diseases such as pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) originates from a complex interplay of environmental factors and genetic predispositions that is not fully understood. Likewise, little is known about developmental abnormalities or epigenetic dysregulations that might predispose for PH or COPD in adult individuals. METHODS: To identify pathology-associated epigenetic alteration in diseased lung tissues, we screened a cohort of human patients with PH and COPD for changes of histone modifications by immunofluorescence staining. To analyze the function of H4K20me2/3 in lung pathogenesis, we developed a series of Suv4-20h1 knockout mouse lines targeting cardiopulmonary progenitor cells and different heart and lung cell types, followed by hemodynamic studies and morphometric assessment of tissue samples. Molecular, cellular, and biochemical techniques were applied to analyze the function of Suv4-20h1-dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives. RESULTS: We discovered a strong reduction of the histone modifications of H4K20me2/3 in human patients with COPD but not patients with PH that depend on the activity of the H4K20 di-methyltransferase SUV4-20H1. Loss of Suv4-20h1 in cardiopulmonary progenitor cells caused a COPD-like/PH phenotype in mice including the formation of perivascular tertiary lymphoid tissue and goblet cell hyperplasia, hyperproliferation of smooth muscle cells/myofibroblasts, impaired alveolarization and maturation defects of the microvasculature leading to massive right ventricular dilatation and premature death. Mechanistically, SUV4-20H1 binds directly to the 5'-upstream regulatory element of the superoxide dismutase 3 (Sod3) gene to repress its expression. Increased levels of the extracellular SOD3 enzyme in Suv4-20h1 mutants increases hydrogen peroxide concentrations, causing vascular defects and impairing alveolarization. CONCLUSIONS: Our findings reveal a pivotal role of the histone modifier SUV4-20H1 in cardiopulmonary codevelopment and uncover the developmental origins of cardiopulmonary diseases. We assume that the study will facilitate the understanding of pathogenic events causing PH and COPD and aid the development of epigenetic drugs for the treatment of cardiopulmonary diseases.

Effects of progesterone on the lipolysis of lipid droplets and prostaglandin E2 synthesis in murine cervical epithelial cells.

Previous studies demonstrated that progesterone (P4) can promote prostaglandin (PG) E2 production; however, how P4 mediates the synthesis of PGE2 remains unclear. In this study, cervical epithelial cells from mice during the follicular phase were cultured invitro and treated with different concentrations of P4 (5, 10, and 20nM). The results of the present study suggest that treatment of murine cervical epithelial cells with 10nM P4 for 24h contributed to: (1) significantly increased expression of protein kinase A (PKA), cytosolic phospholipase A2 (cPLA2) and PGE synthase (PGES)-1; (2) higher phosphorylated (p-) to total extracellular signal-regulated kinase (ERK) 1/2 and hormone-sensitive lipase (HSL) ratios; (3) a significant decrease in the number of lipid droplets (LDs) and fatty acid content within LDs in epithelial cells; and (4) enhanced arachidonic acid and PGE2 levels in cells compared with the control (0nM P4) group (P<0.01 for all findings). In contrast, the PKA inhibitor H89 contributed to significantly decreased cPLA2, PGES-1 and HSL expression, ERK1/2 phosphorylation and arachidonic acid and PGE2 levels, even in the presence of P4. These data show that P4 can act via the PKA/ERK1/2 pathway to stimulate lipolysis of triacylglycerol in the LD core and degradation of phospholipid in the LD membrane to promote PGE2 synthesis in murine cervical epithelial cells.

Characteristics of lipid droplets and the expression of proteins involved in lipolysis in the murine cervix during mid-pregnancy.

Lipid droplets (LDs) are reservoirs of arachidonoyl lipids for prostaglandin (PG) E2 synthesis, and progesterone can stimulate PGE2 synthesis; however, the relationship between progesterone and LD metabolism in the murine cervix remains unclear. In the present study we examined LD distribution and changes in the expression of proteins involved in lipolysis and autophagy in the murine cervix during pregnancy, and compared the findings with those in dioestrous mice. During mid-pregnancy, LDs were predominantly distributed in the cervical epithelium. Electron microscopy revealed the transfer of numerous LDs from the basal to apical region in the luminal epithelium, marked catabolism of LDs, an elevated number of LDs and autophagosomes and a higher LD:mitochondrion size ratio in murine cervical epithelial cells (P<0.05). In addition, immunohistochemical and western blotting analyses showed significantly higher cAMP-dependent protein kinase, adipose triglyceride lipase and hormone-sensitive lipase expression, and a higher light chain 3 (LC3) II:LC3I ratio in the stroma and smooth muscles and, particularly, in murine cervical epithelial cells, during mid-pregnancy than late dioestrus. In conclusion, these results suggest that the enhanced lipolysis of LDs and autophagy in murine cervical tissues were closely related to pregnancy and were possibly controlled by progesterone because LD catabolism may be necessary for energy provision and PGE2 synthesis to maintain a closed pregnant cervix.

Multimodal Regulation of Cardiac Myocyte Proliferation.

Efficient cardiac regeneration is closely associated with the ability of cardiac myocytes to proliferate. Fetal or neonatal mouse hearts containing proliferating cardiac myocytes regenerate even extensive injuries, whereas adult hearts containing mostly post-mitotic cardiac myocytes have lost this ability. The same correlation is seen in some homoiotherm species such as teleost fish and urodelian amphibians leading to the hypothesis that cardiac myocyte proliferation is a major driver of heart regeneration. Although cardiomyocyte proliferation might not be the only prerequisite to restore full organ function after cardiac damage, induction of cardiac myocyte proliferation is an attractive therapeutic option to cure the injured heart and prevent heart failure. To (re)initiate cardiac myocyte proliferation in adult mammalian hearts, a thorough understanding of the molecular circuitry governing cardiac myocyte cell cycle regulation is required. Here, we review the current knowledge in the field focusing on the withdrawal of cardiac myocytes from the cell cycle during the transition from neonatal to adult stages.

Sirtuins in the Cardiovascular System: Potential Targets in Pediatric Cardiology.

Cardiovascular diseases represent a major cause of death and morbidity. Cardiac and vascular pathologies develop predominantly in the aged population in part due to lifelong exposure to numerous risk factors but are also found in children and during adolescence. In comparison to adults, much has to be learned about the molecular pathways driving cardiovascular diseases in the pediatric population. Sirtuins are highly conserved enzymes that play pivotal roles in ensuring cardiac homeostasis under physiological and stress conditions. In this review, we discuss novel findings about the biological functions of these molecules in the cardiovascular system and their possible involvement in pediatric cardiovascular diseases.

Epigenetic modifications of stem cells: a paradigm for the control of cardiac progenitor cells.

Stem cells of all types are characterized by the ability to self-renew and to differentiate. Multiple lines of evidence suggest that both maintenance of stemness and lineage commitment, including determination of the cardiomyogenic lineage, are tightly controlled by epigenetic mechanisms such as DNA methylation, histone modifications, and ATP-dependent chromatin remodeling. Epigenetic mechanisms are intrinsically reversible, interdependent, and highly dynamic in regulation of chromatin structure and specific gene transcription programs, thereby contributing to stem cell homeostasis. Here, we review the current understanding of epigenetic mechanisms involved in regulation of stem cell self-renewal and differentiation and in the control of cardiac progenitor cell commitment during heart development. Further progress in this area will help to decipher the epigenetic landscape in stem and progenitor cells and facilitate manipulation of stem cells for regenerative applications.

Amending the injured heart by in vivo reprogramming.

Ischemic heart injury causes death of cardiomyocyte (CM), formation of a fibrotic scar, and often adverse cardiac remodeling, resulting in chronic heart failure. Therapeutic interventions have lowered myocardial damage and improved heart function, but pharmacological treatment of heart failure has only shown limited progress in recent years. Over the past two decades, different approaches have been pursued to regenerate the heart, by transplantation of newly generated CMs derived from pluripotent stem cells, generation of new CMs by reprogramming of cardiac fibroblasts, or by activating proliferation of preexisting CMs. Here, we summarize recent progress in the development of strategies for in situ generation of new CMs, review recent advances in understanding the underlying mechanisms, and discuss the challenges and future directions of the field.

Effects of Dietary Isoleucine Supplementation on the Production Performance, Health Status and Cecal Microbiota of Arbor Acre Broiler Chickens.

A total of 24,000 healthy 1-day-old Arbor Acres broilers with similar initial weights were used in this study and fed a basal diet supplemented with 0, 400 and 800 mg/kg isoleucine (Ile), denoted CON, ILE400 and ILE800, respectively. Results revealed that the final body weight, average daily weight gain, and eviscerated carcass rate, of broiler chickens in the ILE400 group were significantly higher than in other groups (p < 0.05). In addition, the ILE400 and ILE800 groups had a lower feed conversion rate and a higher survival rate and breast muscle rate (p < 0.05), while the abdominal fat rate was significantly lower than the CON group (p < 0.05). There were significantly lower serum concentrations of UREA, glucose (GLU) and total cholesterol (TCHO) in the ILE400 and ILE800 groups than in the CON group (p < 0.05); glutathione peroxidase (GSH-Px) activity was significantly higher in the ILE400 group than in the other groups, and tumor necrosis factor-alpha (TNF-α) concentration was considerably lower than in other groups (p < 0.05). Moreover, interleukin (IL)-10 concentration in the ILE800 group was significantly higher than in the other groups (p < 0.05). The ILE400 group significantly down-regulated the mRNA expressions of fatty-acid synthase (FASN) and solid alcohol regulatory element binding protein 1c (SREBP1c), and significantly up-regulated the mRNA expressions of adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), lipoprotein lipase (LPL) and sirtuin1 (Sirt1) (p < 0.05). The ILE400 group had significantly higher intestinal villus height than the CON and ILE800 groups, while the ILE800 group had significantly lower intestinal villus height/crypt depth (p < 0.05). Furthermore, high-throughput sequencing showed that the Shannon index, and Verrucomicrobiota, Colidextribacter and Bacteroides abundances were significantly higher in the ILE400 group than in the CON group (p < 0.05). Interestingly, the ILE800 group reduced the Simpson index, phylum Firmicutes and Bacteroidota abundances (including genera Colidextribacter, Butyricicoccus, [Ruminococcus]_torques_group, Bacteroides, Alistipes, Barnesiella and Butyricimonas), and increased Proteobacteria and Cyanobacteria (including genera Dyella, Devosia, unidentified_Chloroplast and Hyphomicrobium) (p < 0.05). Overall, our study showed that adding 400 mg/kg Ile to the diet (diets total Ile levels at 1.01%, 0.90% and 0.87% during the starter, grower and finisher phases, respectively) increased production performance and improved the health status in broiler chickens.

Effects of dietary Galla Chinensis tannin supplementation on immune function and liver health in broiler chickens challenged with lipopolysaccharide.

Herein, Galla Chinensis tannin (GCT) was examined for its influence on preventing lipopolysaccharide (LPS)-induced liver damage in broiler chickens. Approximately 486 one-day-old healthy broilers were randomly allocated to 3 treatment groups (control, LPS, and LPS + GCT). The control and LPS groups were fed a basal diet and the LPS+GCT group was fed the basal diet supplemented with 300 mg/kg GCT. LPS was intraperitoneally injected (1 mg/kg body weight BW) in broilers in the LPS and LPS+GCT groups at 17, 19, and 21 days of age. The results manifested that dietary GCT addition attenuated LPS-induced deleterious effects on serum parameters and significantly increased serum immunoglobulin and complement C3 concentrations relative to the control and LPS groups. Dietary supplementation of GCT inhibited LPS-induced increase in broiler hepatic inflammatory cytokines, caspases activities, and TLR4/NF-κB pathway-related gene mRNA expression. Therefore, 300 mg/kg GCT addition to the diet improved the immune function of broilers and inhibit liver inflammation by blocking the TLR4/NF-κB pathway. Our findings provide support for the application of GCT in poultry production.

FSBP suppresses tumor cell migration by inhibiting the JNK pathway.

The main cause of high mortality in cancer patients is tumor metastasis. Exploring the underlying mechanism of tumor metastasis is of great significance for clinical treatments. Here, we identify the transcription factor Apt/FSBP is a suppressor for tumor metastasis. In Drosophila wing disc, knockdown of apt is able to trigger cell migration, whereas overexpression of apt hampers scrib-RNAi-induced tumor cell migration. Further studies show that loss of apt promotes cell migration through activating the JNK pathway. To investigate the role of FSBP, the homolog of Apt in mammals, we construct Fsbp liver-specific knockout mice. Knockout of Fsbp in liver does not cause any detectable physiological defects, but predisposes to tumorigenesis on DEN and CCl4 treatment. In addition, loss of Fsbp accelerates tumor metastasis from liver to diaphragm. Taken together, this study uncovers FSBP is a novel tumor suppressor, and provides it as a considerable drug target for tumor treatment.

Effects of dietary supplementation with microencapsulated Galla chinensis tannins on growth performance, antioxidant capacity, and lipid metabolism of young broiler chickens.

This study aimed to investigate the impacts of dietary supplementation with Galla chinensis tannins (GCT) on the growth performance, antioxidant capacity, and lipid metabolism of young broilers. Overall, a total of 216 healthy 1 day-old broilers were randomly allocated to CON group and GCT group, and provided with a basal diet or a basal diet added with 300 mg/kg microencapsulated GCT, respectively, in a 21 days trial. Our findings indicated that dietary GCT addition had no significant effects (p > 0.05) on growth performance. However, GCT supplementation led to a significant reduction in the total cholesterol (TC) concentration in the serum and liver (p < 0.05). Furthermore, GCT supplementation significantly increased the ratios of high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and HDL to TC in the serum, in addition to elevating the activities of enzymes related to lipid metabolism in the liver (p < 0.05). Dietary GCT addition also improved the antioxidant capacity of the broilers, as evidenced by a significant decrease in the concentration of malondialdehyde in serum and liver (p < 0.05). Additionally, the GCT group exhibited significantly increased expressions of hepatic genes associated with antioxidant enzymes (HO-1, GPX1, SOD2, SIRT1, CPT-1, and PPARα) (p < 0.05), while the mRNA expression of SREBP-1 was significantly decreased (p < 0.05) compared with the CON group. In conclusion, dietary addition of 300 mg/kg microencapsulated GCT improved the antioxidant status and lipid metabolism of broilers without affecting their growth performance.

The combination of macleaya extract and glucose oxidase improves the growth performance, antioxidant capacity, immune function and cecal microbiota of piglets.

This study aims to investigate the effects of macleaya extract and glucose oxidase combination (MGO) on growth performance, antioxidant capacity, immune function, and cecal microbiota in piglets. A total of 120 healthy 28-day-old weaned piglets were randomly divided into two treatments of six replicates. Piglets were either received a basal diet or a basal diet supplemented with 250 mg/kg MGO (2 g/kg sanguinarine, 1 g/kg chelerythrine, and 1 × 106 U/kg glucose oxidase). The results showed that MGO supplementation increased average daily gain (ADG) and decreased feed:gain ratio (F/G) (p < 0.05). MGO increased serum superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, and immunoglobulin G (IgG) content (p < 0.05), but decreased malondialdehyde (MDA) and interleukin 1ß (IL-1ß) content (p < 0.05). The jejunal mRNA expression of nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 1 (GPX1), and heme oxygenase 1 (HO-1) were increased in MGO group (p < 0.05), while that of kelch like ECH associated protein 1 (Keap1) was decreased (p < 0.05). The Firmicutes was significantly increased at phylum levels in MGO group (p < 0.05). In conclusion, 250 mg/kg MGO improved piglet growth, and regulated intestinal flora of piglets, which provided a theoretical basis for MGO as an alternative additive for antibiotics.

Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine.

Generation of functional transcripts requires transcriptional initiation at regular start sites, avoiding production of aberrant and potentially hazardous aberrant RNAs. The mechanisms maintaining transcriptional fidelity and the impact of spurious transcripts on cellular physiology and organ function have not been fully elucidated. Here we show that TET3, which successively oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and other derivatives, prevents aberrant intragenic entry of RNA polymerase II pSer5 into highly expressed genes of airway smooth muscle cells, assuring faithful transcriptional initiation at canonical start sites. Loss of TET3-dependent 5hmC production in SMCs results in accumulation of spurious transcripts, which stimulate the endosomal nucleic-acid-sensing TLR7/8 signaling pathway, thereby provoking massive inflammation and airway remodeling resembling human bronchial asthma. Furthermore, we found that 5hmC levels are substantially lower in human asthma airways compared with control samples. Suppression of spurious transcription might be important to prevent chronic inflammation in asthma.

Nucleolar disruption in dopaminergic neurons leads to oxidative damage and parkinsonism through repression of mammalian target of rapamycin signaling.

The nucleolus represents an essential stress sensor for the cell. However, the molecular consequences of nucleolar damage and their possible link with neurodegenerative diseases remain to be elucidated. Here, we show that nucleolar damage is present in both genders in Parkinson's disease (PD) and in the pharmacological PD model induced by the neurotoxin 1,2,3,6-tetrahydro-1-methyl-4-phenylpyridine hydrochloride (MPTP). Mouse mutants with nucleolar disruption restricted to dopaminergic (DA) neurons show phenotypic alterations that resemble PD, such as progressive and differential loss of DA neurons and locomotor abnormalities. At the molecular level, nucleolar disruption results in increased p53 levels and downregulation of mammalian target of rapamycin (mTOR) activity, leading to mitochondrial dysfunction and increased oxidative stress, similar to PD. In turn, increased oxidative stress induced by MPTP causes mTOR and ribosomal RNA synthesis inhibition. Collectively, these observations suggest that the interplay between nucleolar dysfunction and increased oxidative stress, involving p53 and mTOR signaling, may constitute a destructive axis in experimental and sporadic PD.

Immunolocalization of adipocytes and prostaglandin E2 and its four receptor proteins EP1, EP2, EP3, and EP4 in the caprine cervix during spontaneous term labor.

The mechanisms of cervical ripening and dilation in mammals remain obscure. Information is lacking about the localization of prostaglandin E(2) (PGE(2))-producing cells and PGE(2) receptors (EP) in intrapartum cervix and whether cervical dilation at parturition is an active process. To reveal these mechanisms, immunolocalization of EP1-EP4 (official gene symbols PTGER1-PTGER4) and PGE(2)-producing cells in caprine cervix during nonpregnancy, pregnancy, and parturition was assayed by immunohistochemistry (IHC); the mRNA expression levels of PTGS2, PTGER2 (EP2), and PTGER4 (EP4) were determined using quantitative PCR; and the existence of adipocytes in the cervix at various stages was demonstrated with Oil Red O staining and IHC of perilipin A. The results suggested that in intrapartum caprine cervix staining of the PGE(2) was observed in the overall tissues, for example, blood vessels, canal or glandular epithelia, serosa, circular and longitudinal muscles, and stroma in addition to adipocytes; EP2 was detectable in all the tissues other than glandular epithelia; EP4 was strongly expressed in all the tissues other than serosa; EP1 was detected mainly in arterioles and canal or glandular epithelia; and EP3 was poorly expressed only in stroma, canal epithelia, and circular muscles. Little or no expression of EP2, EP3, and EP4 as well as PGE(2) in all cervical tissues was observed during nonpregnancy and pregnancy except for the strong expression of EP1 in canal or glandular epithelia during pregnancy. The mRNA expression levels of PTGS2, PTGER2, and PTGER4 were significantly higher in intrapartum than nonpregnant and midpregnant cervices (P < 0.01). Adipocytes appear only in the intrapartum cervix. These results support the concept that PGE(2) modulates specific functions in various anatomical structures of the caprine cervix at labor and the appearance of adipocytes at labor is likely related to caprine cervical dilation.

Replication collisions induced by de-repressed S-phase transcription are connected with malignant transformation of adult stem cells.

Transcription replication collisions (TRCs) constitute a major intrinsic source of genome instability but conclusive evidence for a causal role of TRCs in tumor initiation is missing. We discover that lack of the H4K20-dimethyltransferase KMT5B (also known as SUV4-20H1) in muscle stem cells de-represses S-phase transcription by increasing H4K20me1 levels, which induces TRCs and aberrant R-loops in oncogenic genes. The resulting replication stress and aberrant mitosis activate ATR-RPA32-P53 signaling, promoting cellular senescence, which turns into rapid rhabdomyosarcoma formation when p53 is absent. Inhibition of S-phase transcription ameliorates TRCs and formation of R-loops in Kmt5b-deficient MuSCs, validating the crucial role of H4K20me1-dependent, tightly controlled S-phase transcription for preventing collision errors. Low KMT5B expression is prevalent in human sarcomas and associated with tumor recurrence, suggesting a common function of KMT5B in sarcoma formation. The study uncovers decisive functions of KMT5B for maintaining genome stability by repressing S-phase transcription via control of H4K20me1 levels.

Quantitative Proteomic Analysis of Zearalenone Exposure on Uterine Development in Weaned Gilts.

The aim of this study was to explore the effect of zearalenone (ZEA) exposure on uterine development in weaned gilts by quantitative proteome analysis with tandem mass spectrometry tags (TMT). A total of 16 healthy weaned gilts were randomly divided into control (basal diet) and ZEA3.0 treatments groups (basal diet supplemented with 3.0 mg/kg ZEA). Results showed that vulva size and uterine development index were increased (p < 0.05), whereas serum follicle stimulation hormone, luteinizing hormone and gonadotropin-releasing hormone were decreased in gilts fed the ZEA diet (p < 0.05). ZEA, α-zearalenol (α-ZOL) and ß-zearalenol (ß-ZOL) were detected in the uteri of gilts fed a 3.0 mg/kg ZEA diet (p < 0.05). The relative protein expression levels of creatine kinase M-type (CKM), atriopeptidase (MME) and myeloperoxidase (MPO) were up-regulated (p < 0.05), whereas aldehyde dehydrogenase 1 family member (ALDH1A2), secretogranin-1 (CHGB) and SURP and G-patch domain containing 1 (SUGP1) were down-regulated (p < 0.05) in the ZEA3.0 group by western blot, which indicated that the proteomics data were dependable. In addition, the functions of differentially expressed proteins (DEPs) mainly involved the cellular process, biological regulation and metabolic process in the biological process category. Some important signaling pathways were changed in the ZEA3.0 group, such as extracellular matrix (ECM)-receptor interaction, focal adhesion and the phosphoinositide 3-kinase−protein kinase B (PI3K-AKT) signaling pathway (p < 0.01). This study sheds new light on the molecular mechanism of ZEA in the uterine development of gilts.