Mammalian fertilization begins with the fusion of two specialized gametes, followed by major epigenetic remodeling leading to the formation of a totipotent embryo. During the development of the pre-implantation embryo, precise reprogramming progress is a prerequisite for avoiding developmental defects or embryonic lethality, but the underlying molecular mechanisms remain elusive. For the past few years, unprecedented breakthroughs have been made in mapping the regulatory network of dynamic epigenomes during mammalian early embryo development, taking advantage of multiple advances and innovations in low-input genome-wide chromatin analysis technologies. The aim of this review is to highlight the most recent progress in understanding the mechanisms of epigenetic remodeling during early embryogenesis in mammals, including DNA methylation, histone modifications, chromatin accessibility and 3D chromatin organization.
Animals ; Chromatin Assembly and Disassembly ; DNA Methylation ; DNA Transposable Elements ; Embryo, Mammalian ; Embryonic Development/genetics* ; Epigenesis, Genetic ; Epigenome ; Female ; Fertilization/physiology* ; Gene Expression Regulation, Developmental ; Histone Code ; Histones/metabolism* ; Male ; Mice ; Oocytes/metabolism* ; Spermatozoa/metabolism*

Long noncoding RNA (lncRNA) is once thought to be the genome transcriptional "noise". However, it has received considerable attention in the past few years and is emerging as potentially important player in biological regulation. Recent studies have revealed that increasing number of lncRNA plays pivotal roles in regulating the gene expression which involves in the development of the human disease. Functions of lncRNA include 3 types of interaction: RNA-RNA, RNA-DNA, and RNA-protein, which may participate in gene expression regulation through epigenetic modifications, transcriptional regulation, post-transcriptional regulation, acting as biological media. Due to the prevalence of obesity and related diseases, some attempts have been done to explore the pathogenesis of obesity from the field of noncoding RNA. Several lncRNAs have been identified to be involved in the regulation of the adipogenesis (white adipose tissue and brown adipose tissue) and energy metabolism. In this review, we summarized recent advances of lncRNAs to provide a new sight for the mechanism of obesity.
Adipogenesis ; genetics ; Epigenesis, Genetic ; Gene Expression Regulation ; Humans ; RNA, Long Noncoding ; physiology ; RNA, Untranslated

Epigenetic factors play an important role in male infertility though about 60%－65% of the disease is idiopathic and its underlying causes are not yet clear. Many studies have indicated that epigenetic modifications, including DNA methylation, histone tail modifications, chromatin remodeling, and non-coding RNAs, may be involved in idiopathic male infertility. Abnormal methylation is associated with decreased sperm quality and fertility. It is known that 1 881 miRNAs are related to male fertility and such non-coding RNAs as piRNA, IncRNA, and circRNA play a regulating role in male reproduction. This review focuses on the value of epigenetics in the etiology and pathogenesis of male infertility, aiming to provide some evidence for the establishment of some strategies for the treatment and prediction of the disease.
DNA Methylation ; Epigenesis, Genetic ; Fertility ; Humans ; Infertility, Male ; genetics ; Male ; MicroRNAs ; physiology ; RNA, Small Interfering ; Spermatozoa

BACKGROUNDThe acute myeloid leukemia 1 (AML1)-eight-twenty-one (ETO) fusion protein generated by the t(8;21)(q22;q22) translocation is considered to display a crucial role in leukemogenesis in AML. By focusing on the anti-leukemia effects of eyes absent 4 (EYA4) gene on AML cells, we investigated the biologic and molecular mechanism associated with AML1-ETO expressed in t(8;21) AML.

METHODSQualitative polymerase chain reaction (PCR), quantitative reverse transcription PCR (RT-PCR), and Western blotting analysis were used to observe the mRNA and protein expression levels of EYA4 in cell lines. Different plasmids (including mutant plasmids) of dual luciferase reporter vector were built to study the binding status of AML1-ETO to the promoter region of EYA4. Chromatin immunoprecipitation assay was used to study the epigenetic silencing mechanism of EYA4. Bisulfite sequencing was applied to detect the methylation status in EYA4 promoter region. The influence of EYA4 gene in the cell proliferation, apoptosis, and cell clone-forming ability was detected by the technique of Cell Counting Kit-8, flow cytometry, and clonogenic assay.

RESULTSEYA4 gene was hypermethylated in AML1-ETO+ patients and its expression was down-regulated by 6-fold in Kasumi-1 and SKNO-1 cells, compared to HL-60 and SKNO-1-siA/E cells, respectively. We demonstrated that AML1-ETO triggered the epigenetic silencing of EYA4 gene by binding at AML1-binding sites and recruiting histone deacetylase 1 and DNA methyltransferases. Enhanced EYA4 expression levels inhibited cellular proliferation and suppressed cell colony formation in AML1-ETO+ cell lines. We also found EYA4 transfection increased apoptosis of Kasumi-1 and SKNO-1 cells by 1.6-fold and 1.4-fold compared to negative control, respectively.

CONCLUSIONSOur study identified EYA4 gene as targets for AML1-ETO and indicated it as a novel tumor suppressor gene. In addition, we provided evidence that EYA4 gene might be a novel therapeutic target and a potential candidate for treating AML1-ETO+ t (8;21) AML.

Apoptosis ; genetics ; physiology ; Blotting, Western ; Cell Line, Tumor ; Cell Proliferation ; genetics ; physiology ; Chromatin Immunoprecipitation ; Core Binding Factor Alpha 2 Subunit ; genetics ; metabolism ; DNA Methylation ; genetics ; Epigenesis, Genetic ; genetics ; Gene Silencing ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute ; genetics ; metabolism ; pathology ; Oncogene Proteins, Fusion ; genetics ; metabolism ; RNA, Small Interfering ; genetics ; RUNX1 Translocation Partner 1 Protein ; Radioimmunoprecipitation Assay ; Trans-Activators ; genetics ; metabolism

Heart is the first organ to function during mammalian embryogenesis. The differentiation of embryonic stem cells (ESCs) into cardiomyocyte is complex and dynamic, which involves 4 differentiation stages including ESCs, mesoderm, cardiac precursor, and terminal cardiomyocytes. Abnormal expression of certain genes can lead to congenital heart diseases during cardiomyocyte differentiation. Epigenetic regulation plays a crucial role on the switch of gene activation and deactivation during cardiomyocyte differentiation. Non-coding RNA, particularly microRNA and long non-coding RNA, may significantly influence gene expression. Exploring the regulatory roles of non-coding RNA in cardiomyocyte differentiation may contribute to the understanding of the functions of myocardial cells and mechanism of congenital heart diseases.
Animals ; Cell Differentiation ; genetics ; Embryo, Mammalian ; physiology ; Embryonic Stem Cells ; physiology ; Epigenesis, Genetic ; genetics ; Humans ; Myocytes, Cardiac ; physiology ; RNA, Long Noncoding ; genetics

The occurrence and development of acute myeloid leukemia (AML) is not only related to gene mutations, but also influenced by abnormal epigenetic regulation, in which DNA methylation is one of the most important mechanisms. Abnormal DNA methylation may lead to the activation of oncogene and the inactivation of tumor suppressor gene, resulting in the occurrence of leukemia. The mutations of DNA methylation enzymes associated with AML may have certain characteristics. The AML with recurrent cytogenetic abnormalities is also related to abnormal methylation. Some fusion genes can alter DNA methylation status to participate in the pathogenesis of leukemia. In addition, chemotherapy drug resistance in patients with AML is associated with the change of gene methylation status. Considering the reversibility of the epigenetic modification, targeted methylation therapy has become a hotspot of AML research.
DNA Methylation ; drug effects ; genetics ; physiology ; DNA Modification Methylases ; genetics ; physiology ; Drug Resistance, Neoplasm ; genetics ; Epigenesis, Genetic ; genetics ; physiology ; Humans ; Leukemia, Myeloid, Acute ; etiology ; genetics ; pathology ; Mutation ; genetics

Gastric cancer(GC) is a highly heterogeneous malignancy. The present widely used histopathological classifications have gradually failed to meet the needs of individualized diagnosis and treatment. Development of technologies such as microarray and next-generation sequencing (NGS) has allowed GC to be studied at the molecular level. Mechanisms about tumorigenesis and progression of GC can be elucidated in the aspects of gene mutations, chromosomal alterations, transcriptional and epigenetic changes, on the basis of which GC can be divided into several subtypes. The classifications of Tan's, Lei's, TCGA and ACRG are relatively comprehensive. Especially the TCGA and ACRG classifications have large sample size and abundant molecular profiling data, thus, the genomic characteristics of GC can be depicted more accurately. However, significant differences between both classifications still exist so that they cannot be substituted for each other. So far there is no widely accepted molecular classification of GC. Compared with TCGA classification, ACRG system may have more clinical significance in Chinese GC patients since the samples are mostly from Asian population and show better association with prognosis. The molecular classification of GC may provide the theoretical and experimental basis for early diagnosis, therapeutic efficacy prediction and treatment stratification while their clinical application is still limited. Future work should involve the application of molecular classifications in the clinical settings for improving the medical management of GC.
Asian Continental Ancestry Group ; Carcinogenesis ; genetics ; Disease Progression ; Early Detection of Cancer ; Epigenesis, Genetic ; physiology ; High-Throughput Nucleotide Sequencing ; Humans ; Microarray Analysis ; Molecular Epidemiology ; standards ; Mutation ; physiology ; Prognosis ; Stomach Neoplasms ; classification ; genetics

Mesenchymal stem cells (MSCs) are characterized by their self-renewing capacity and differentiation potential into multiple tissues. Thus, management of the differentiation capacities of MSCs is important for MSC-based regenerative medicine, such as craniofacial bone regeneration, and in new treatments for metabolic bone diseases, such as osteoporosis. In recent years, histone modification has been a growing topic in the field of MSC lineage specification, in which the Su(var)3-9, enhancer-of-zeste, trithorax (SET) domain-containing family and the Jumonji C (JmjC) domain-containing family represent the major histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs), respectively. In this review, we summarize the current understanding of the epigenetic mechanisms by which SET domain-containing KMTs and JmjC domain-containing KDMs balance the osteogenic and adipogenic differentiation of MSCs.
Adipogenesis ; genetics ; physiology ; Cell Differentiation ; genetics ; physiology ; Cell Lineage ; genetics ; Epigenesis, Genetic ; genetics ; F-Box Proteins ; genetics ; physiology ; Histone Demethylases ; genetics ; physiology ; Histone-Lysine N-Methyltransferase ; genetics ; physiology ; Humans ; Jumonji Domain-Containing Histone Demethylases ; genetics ; physiology ; Mesenchymal Stromal Cells ; enzymology ; physiology ; Methyltransferases ; genetics ; physiology ; Osteogenesis ; genetics ; physiology

Histone methylation is one of the most widely studied post-transcriptional modifications. It is thought to be an important epigenetic event that is closely associated with cell fate determination and differentiation. To explore the spatiotemporal expression of histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 27 trimethylation (H3K27me3) epigenetic marks and methylation or demethylation transferases in tooth organ development, we measured the expression of SET7, EZH2, KDM5B and JMJD3 via immunohistochemistry and quantitative polymerase chain reaction (qPCR) analysis in the first molar of BALB/c mice embryos at E13.5, E15.5, E17.5, P0 and P3, respectively. We also measured the expression of H3K4me3 and H3K27me3 with immunofluorescence staining. During murine tooth germ development, methylation or demethylation transferases were expressed in a spatial-temporal manner. The bivalent modification characterized by H3K4me3 and H3K27me3 can be found during the tooth germ development, as shown by immunofluorescence. The expression of SET7, EZH2 as methylation transferases and KDM5B and JMJD3 as demethylation transferases indicated accordingly with the expression of H3K4me3 and H3K27me3 respectively to some extent. The bivalent histone may play a critical role in tooth organ development via the regulation of cell differentiation.
Animals ; Cell Differentiation ; physiology ; DNA-Binding Proteins ; analysis ; Dental Papilla ; embryology ; Embryo, Mammalian ; Enamel Organ ; embryology ; Enhancer of Zeste Homolog 2 Protein ; Epigenesis, Genetic ; physiology ; Gene Expression Regulation, Developmental ; Histone-Lysine N-Methyltransferase ; analysis ; Histones ; metabolism ; Jumonji Domain-Containing Histone Demethylases ; analysis ; Lysine ; metabolism ; Methylation ; Mice ; Mice, Inbred BALB C ; Odontogenesis ; physiology ; Polycomb Repressive Complex 2 ; analysis ; Protein Processing, Post-Translational ; physiology ; Tooth Germ ; embryology

Animals ; Epigenesis, Genetic ; genetics ; Fetal Development ; genetics ; physiology ; Glucose ; metabolism ; Humans ; MicroRNAs ; genetics ; metabolism