炎症性肠病的自噬与表观遗传修饰

文题释义：自噬：是一个吞噬自身细胞质蛋白或细胞器并使其包被进入囊泡,并与溶酶体融合形成自噬溶酶体,降解其所包裹的内容物的过程,以此实现细胞本身的代谢需要和某些细胞器的更新。 表观遗传：是指DNA序列不发生变化,但基因表达却发生了可遗传的改变,主要包括DNA甲基化、组蛋白修饰、染色质重塑以及非编码RNA的调控,这种改变在细胞发育和增殖过程中能稳定的传递。 背景：炎症性肠病是一种与肠道自身免疫相关的慢性炎症性疾病,自噬是促进免疫调节的细胞途径,相关基因的表达异常与肠道炎症以及免疫反应关系密切,而表观遗传修饰对炎症性肠病自噬的调控机制尚未阐明。 目的：文章旨在对表观遗传修饰在炎症性肠病自噬中的调控作用作一介绍,以期探讨炎症性肠病自噬的发生机制。 方法：检索PubMed数据库,检索时限1998年1月至2019年4月,检索关键词为“inflammatory bowel disease,autophagy,autophagy related genes,epigenetic modification,DNA methylation,histone modification,chromatin remodeling,miRNA”,选择61篇符合标准的文献。 结果与结论：表观遗传(DNA甲基化、组蛋白修饰、染色质重塑、非编码RNA)可通过修饰炎症性肠病的易感基因ATG、IRGM等来调控肠道炎症、免疫以及自噬,从而介导炎症性肠病的发生和发展。 ORCID: 0000-0003-0627-9236(郭娅静) 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

Chromatinopathies: A focus on Cornelia de Lange syndrome

In recent years, many genes have been associated with chromatinopathies classified as “Cornelia de Lange Syndrome-like.” It is known that the phenotype of these patients becomes less recognizable, overlapping to features characteristic of other syndromes caused by genetic variants affecting different regulators of chromatin structure and function. Therefore, Cornelia de Lange syndrome diagnosis might be arduous due to the seldom discordance between unexpected molecular diagnosis and clinical evaluation. Here, we review the molecular features of Cornelia de Lange syndrome, supporting the hypothesis that “CdLS-like syndromes” are part of a larger “rare disease family” sharing multiple clinical features and common disrupted molecular pathways.     

Histone deacetylase activity is necessary for chromosome condensation during meiotic maturation in Xenopus laevis

Chromosome condensation is thought to be an essential step for the faithful transmission of genetic information during cellular division or gamete formation. The folding of DNA into metaphase chromosomes and its partition during the cell cycle remains a fundamental cellular process that, at the molecular level, is poorly understood. Particularly, the role of histone deacetylase (HDAC) activities in establishing and maintaining meiotic metaphase chromosome condensation has been little documented. In order to better understand how metaphase chromosome condensation is achieved during meiosis, we explored, in vivo, the consequences of HDAC activities inhibition in a Xenopus oocyte model. Our results show that deacetylase activity plays a crucial role in chromosome condensation. This activity is necessary for correct chromosome condensation since the earlier stages of meiosis, but dispensable for meiosis progression, meiosis exit and mitosis entry. We show that HDAC activity correlates with chromosome condensation, being higher when chromosomes are fully condensed and lower during interphase, when chromosomes are decondensed. In addition, we show that, unlike histone H4, Xenopus maternal histone H3 is stored in the oocyte as a hypoacetylated form and is rapidly acetylated when the oocyte exits meiosis.     

Chromatin architectural proteins

The accessibility of eukaryotic DNA is dependent upon the hierarchical level of chromatin organization. These include (1) intra-nucleosome interactions, (2) inter-nucleosome interactions and (3) the influence of non-histone chromatin architectural proteins. There appears to be interplay between all these levels, in that one level can override another or that two or more can act in concert. In the first level, the stability of the nucleosome itself is dependent on the number and type of contacts between the core histones and the surrounding DNA, as well as protein–protein interactions within the core histone octamer. Core histone variants, post-translational modifications of the histones, and linker histones binding to the DNA all influence the organization and stability of the nucleosome. When nucleosomes are placed end-to-end in linear chromatin arrays, the second level of organization is revealed. The amino terminal tails of the histone proteins make contacts with adjacent and distant nucleosomes, both within the fiber and between different fibers. The third level of organization is imposed upon these ‘intrinsic’ constraints, and is due to the influence of chromatin binding proteins that alter the architecture of the underlying fiber. These chromatin architectural proteins can, in some cases, bypass intrinsic constraints and impart their own topological affects, resulting in truly unique, supra-molecular assemblages that undoubtedly influence the accessibility of the underlying DNA. In this review we will provide a brief summary of what has been learned about the intrinsic dynamics of chromatin fibers, and survey the biology and architectural affects of the handful of chromatin architectural proteins that have been identified and characterized. These proteins are likely only a small subset of the architectural proteins encoded within the eukaryotic genome. We hope that an increased understanding and appreciation of the contribution of these proteins to genome accessibility will hasten the identification and characterization of more of these important regulatory factors.     

Distinct microtubule and chromatin characteristics of human oocytes after failed in-vivo and in-vitro meiotic maturation

BACKGROUND: While a complete failure of meiotic maturation following hCG administration is rare during IVF cycles, cases arise in which patients repeatedly display a high incidence of failure to complete maturation to metaphase II (MII) in vivo. For the immature oocytes of such patients, our objectives were (i) to ask whether progression to MII could be supported in vitro, and (ii) to define their microtubule/chromatin properties following in-vitro maturation (IVM). Together, these studies were aimed at augmenting our understanding of factors underlying meiotic arrest in the human. METHODS: Cases are presented here for two patients (A and B) producing oocytes that recurrently showed the inability to mature to metaphase II in vivo. Following IVM attempts, chromatin and microtubule characteristics were identified in those oocytes that remained arrested during meiosis I. RESULTS: In patient A, meiotically arrested oocytes exhibited clear defects in spindle and chromatin arrangements. In contrast, the majority of oocytes from patient B displayed normal MI and MII spindles with aligned chromosomes, although some oocytes exhibited indications for possible defects in cell cycle control. CONCLUSIONS: Together, these analyses illustrate two cases with oocytes exhibiting a common gross defect, that is meiotic maturation arrest, but revealing different aetiologies or manifestations as evidenced by the presence or absence of abnormal spindle/chromatin organization. This work reinforces the existence of intrinsic defects in oocytes of some patients, the molecular and cellular bases of which merit further investigation.     

Conservation of chromosome arrangement and position of the X in mammalian sperm suggests functional significance

We used chromosome painting to show directly that chromosomes occupy fixed positions in the nuclei of mammal but not chicken sperm. We found that the positions of homologous chromosomes are conserved in sperm of two marsupial species that diverged 50–60 million years ago. We also discovered that the X chromosome lies in the region that makes first contact with the egg in marsupial and monotreme mammals, as well as eutherians, and suggest that this position may be related to its propensity for inactivation, and its high rate of loss from ICSI embryos. We propose that nuclear architecture in sperm is important for spatial chromatin differentiation and normal development of the fertilized egg, and evolved along with mammal-specific regulatory systems such as X inactivation and genomic imprinting. This revised version was published online in July 2006 with corrections to the Cover Date.     

The role of the chromatin remodeler Mi-2beta in hematopoietic stem cell self-renewal and multilineage differentiation

The ability of somatic stem cells to self-renew and differentiate into downstream lineages is dependent on specialized chromatin environments that keep stem cell-specific genes active and key differentiation factors repressed but poised for activation. The epigenetic factors that provide this type of regulation remain ill-defined. Here we provide the first evidence that the SNF2-like ATPase Mi-2beta of the Nucleosome Remodeling Deacetylase (NuRD) complex is required for maintenance of and multilineage differentiation in the early hematopoietic hierarchy. Shortly after conditional inactivation of Mi-2beta, there is an increase in cycling and a decrease in quiescence in an HSC (hematopoietic stem cell)-enriched bone marrow population. These cycling mutant cells readily differentiate into the erythroid lineage but not into the myeloid and lymphoid lineages. Together, these effects result in an initial expansion of mutant HSC and erythroid progenitors that are later depleted as more differentiated proerythroblasts accumulate at hematopoietic sites exhibiting features of erythroid leukemia. Examination of gene expression in the mutant HSC reveals changes in the expression of genes associated with self-renewal and lineage priming and a pivotal role of Mi-2beta in their regulation. Thus, Mi-2beta provides the hematopoietic system with immune cell capabilities as well as with an extensive regenerative capacity.