Mechanisms of histone H3 lysine 27 trimethylation remodeling during early mammalian development

During fertilization, two of the most differentiated cells in the mammalian organism, a sperm and oocyte, are combined to form a pluripotent embryo. Dynamic changes in chromatin structure allow the transition of the chromatin on these specialized cells into an embryonic configuration capable of generating every cell type. Initially, this reprogramming activity is supported by oocyte-derived factors accumulated during oogenesis as proteins and mRNAs; however, the underlying molecular mechanisms that govern it remain poorly characterized. Trimethylation of histone H3 at lysine 27 (H3K27me3) is a repressive epigenetic mark that changes dynamically during pre-implantation development in mice, bovine and pig embryos. Here we present data and hypotheses related to the potential mechanisms behind H3K27me3 remodeling during early development. We postulate that the repressive H3K27me3 mark is globally erased from the parental genomes in order to remove the gametic epigenetic program and to establish a pluripotent embryonic epigenome. We discuss information gathered in mice, pigs, and bovine, with the intent of providing a comparative analysis of the reprogramming of this epigenetic mark during early mammalian development.     

Mechanisms of histone H3 lysine 27 trimethylation remodeling during early mammalian development

During fertilization, two of the most differentiated cells in the mammalian organism, a sperm and oocyte, are combined to form a pluripotent embryo. Dynamic changes in chromatin structure allow the transition of the chromatin on these specialized cells into an embryonic configuration capable of generating every cell type. Initially, this reprogramming activity is supported by oocyte-derived factors accumulated during oogenesis as proteins and mRNAs; however, the underlying molecular mechanisms that govern it remain poorly characterized. Trimethylation of histone H3 at lysine 27 (H3K27me3) is a repressive epigenetic mark that changes dynamically during pre-implantation development in mice, bovine and pig embryos. Here we present data and hypotheses related to the potential mechanisms behind H3K27me3 remodeling during early development. We postulate that the repressive H3K27me3 mark is globally erased from the parental genomes in order to remove the gametic epigenetic program and to establish a pluripotent embryonic epigenome. We discuss information gathered in mice, pigs, and bovine, with the intent of providing a comparative analysis of the reprogramming of this epigenetic mark during early mammalian development.     

Histone variants in metazoan development

Embryonic development is regulated by both genetic and epigenetic mechanisms, with nearly all DNA-templated processes influenced by chromatin architecture. Sequence variations in histone proteins, core components of chromatin, provide a means to generate diversity in the chromatin structure, resulting in distinct and profound biological outcomes in the developing embryo. Emerging literature suggests that epigenetic contributions from histone variants play key roles in a number of developmental processes such as the initiation and maintenance of pericentric heterochromatin, X-inactivation, and germ cell differentiation. Here, we review the role of histone variants in the embryo with particular emphasis on early mammalian development.     

Chromatin remodeling in development and differentiation

During development and differentiation, early inductive processes that influence cell fate at a later stage leave marks at distinct gene loci that are maintained through several rounds of mitosis. The structure of chromatin is part of this epigenetic memory that restricts or permits differential expression of genes in descendant cells. Establishing a cell-type-specific chromatin pattern thus predestines future cell differentiation and deters cell-lineage infidelity, as it often occurs during neoplastic transformation. As such, understanding the dynamics and mechanisms underlying chromatin remodeling has been a major focus of recent molecular genetic research that holds great promise for biomedical discoveries.     

Epigenetic programming: from gametes to blastocyst

Embryo development requires a series of cell fate decisions; cell lineages are established early during development and must be "remembered" through multiple cell divisions. It is increasingly evident that epigenetic marks, DNA methylation, histone modifications, and noncoding RNAs, have a critical role in this cell memory during development. During gametogenesis, epigenetic programming results in the production of spermatozoa and oocytes with distinctive chromatin. The goal of this article is to review what is known about the epigenetic marks in mature gametes and how these marks change during early embryo development. An understanding of the role of epigenetic programming during normal development will lay the basis for the elucidation of its role when development goes awry and the consequence is a birth defect.     

高等植物中SWI/SNF染色质重塑研究的新进展

染色质重塑是真核生物表观遗传调控的重要方式．通过对染色质物理结构的调节,染色质重塑在高等动植物干细胞的自我更新及分化、器官和个体发育以及肿瘤发生等多种生物学过程中发挥重要作用．近年来,高等动植物染色质重塑方面的研究已经成为表观遗传学研究领域的热点．本综述总结近年来有关高等动植物染色质重塑的重要研究报道,介绍了染色质重塑的结构机制、分析比较了高等动植物染色质重塑复合体的组成及其生物学功能的多样性,并着重综述了高等植物SWI/SNF染色质重塑复合体各组分在调控植物发育与逆境生长等方面的功能,以期为今后植物中染色质重塑的研究提供启示．     

Characterization of non-canonical Polycomb Repressive Complex 1 subunits during early mouse embryogenesis

An intense period of chromatin remodeling takes place after fertilization in mammals, which is thought necessary for epigenetic reprogramming to start a new developmental program. While much attention has been given to the role of Polycomb Repressive Complex 2 (PRC2) and to canonical PRC1 complexes during this process, little is known as to whether there is any contribution of non-canonical PRC1 in shaping the chromatin landscape after fertilization. Here, we first describe in detail the temporal dynamics and abundance of H2A ubiquitylation (H2AK119ub), a histone modification catalyzed by PRC1, during pre-implantation mouse development. In addition, we have analyzed the presence of the 2 characteristic subunits of non-canonical PRC1 complexes, RYBP and its homolog YAF-2. Our results indicate that H2AK119ub is inherited from the sperm, rapidly removed from the paternal chromatin after fertilization, but detected again prior to the first mitosis, suggesting that PRC1 activity occurs as early as the zygotic stage. RYBP and YAF-2, together with the non-canonical subunit L3MBTL2, are all present during pre-implantation development but show different temporal dynamics. While RYBP is absent in the zygote, it is strongly induced from the 4-cell stage onwards. YAF-2 is inherited maternally and localizes to the pericentromeric regions in the zygote, is strongly induced between the 2- and 4-cell stages but then remains weak to undetectable subsequently. All together, our data suggest that non-canonical PRC1 is active during pre-implantation development and should be regarded as an additional component during epigenetic reprogramming and in the establishment of cellular plasticity of the early embryo.     

Sperm chromatin remodeling after intracytoplasmic sperm injection differs from that of in vitro fertilization

Intracytoplasmic sperm injection (ICSI) is a popular method used in assisted conception, and live offspring have been born from a variety of species, including humans. In ICSI, sperm chromatin is introduced into the oocyte together with the acrosome, a structure that does not enter the oocyte during normal fertilization. We compared sperm chromatin remodeling, the potential of embryos to develop in vitro, and DNA synthesis in mouse embryos obtained from in vitro fertilization (IVF) and ICSI. We also tested whether sperm pretreatment prior to ICSI (i.e., capacitation, acrosome reaction, membrane removal, and reduction of disulfide bonds in protamines) facilitates chromatin remodeling and affects embryo development. Sperm chromatin was examined on air-dried, Giemsa-stained preparations at 30-min intervals for up to 4.5 h postfertilization. In all experimental groups, the oocytes underwent activation and formed pronuclei with similar rates. However, the dynamics of sperm chromatin remodeling in ICSI and IVF embryos varied. In ICSI, chromatin remodeling was more asynchronous than in IVF. Sperm capacitation prior to injection enhanced remodeling asynchrony and resulted in delayed pronuclei formation and DNA synthesis. The removal of the acrosome prior to injection with calcium ionophore A23187 but not with detergent Triton X-100 allowed more synchronous chromatin remodeling, timely DNA synthesis, and good embryo development. Our data have significance for the refinement of the molecular and biologic mechanisms associated with ICSI for current and future applications.     

抗原受体基因重组的表观遗传学调控研究新进展

淋巴细胞是哺乳动物唯一能发生体细胞基因组变化的一类细胞,淋巴细胞在发育过程中通过V(D)J重组获得成熟的特异的抗原受体基因,实现了免疫细胞抗原识别惊人的多样性.关于V(D)J重组的调控机制一直是免疫学研究的重要问题,然而直到将表观遗传学研究引入这一领域,综合遗传学和表观遗传学的研究才真正揭示V(D)J重组精细的调控机制.综述了新近发现的V(D)J重组过程中重要的表观遗传学调控机制,如CpG甲基化,组蛋白修饰,核小体重塑及核拓扑学变化.     

Maternal influences on epigenetic programming of the developing hypothalamic-pituitary-adrenal axis

Parental and environmental factors during the prenatal and postnatal periods permanently affect the physiology and metabolism of offspring, potentially increasing disease risk later in life. Underlying mechanisms are being elucidated, and effects on a number of organs and metabolic pathways are likely involved. In this review, we consider effects on the developing hypothalamic-pituitary-adrenal (HPA) axis, which may represent a common pathway for developmental programming. The focus is on prenatal and early postnatal development, during which the HPA axis may be programmed in a manner that affects health for a lifetime. Programming of the HPA axis involves, at least in part, epigenetic remodeling of chromatin, leading to alterations in the expression of genes in many organs and tissues involved in HPA activation and response, including the hippocampus and peripheral tissues. Examples of developmental epigenetic modifications affecting the HPA axis as well as target tissues are provided.