Quantitative epigenetics: DNA sequence variation need not apply

Two recent reports, including one by Reinders and colleagues (pp. 939–950) in the April 15, 2009, issue of Genes & Development, describe the construction of Arabidopsis recombinant inbred populations that maximize epigenetic rather than genetic variation. The distribution and behavior of phenotypic variation in these populations suggest that stable epialleles can control complex quantitative traits. However, stochastic epimutation and transposon movement in these populations present some unexpected technical hurdles to implementing quantitative epigenetic analysis.     

Common epigenetic changes of D4Z4 in contraction‐dependent and contraction‐independent FSHD

Facioscapulohumeral muscular dystrophy (FSHD), caused by partial deletion of the D4Z4 macrosatellite repeat on chromosome 4q, has a complex genetic and epigenetic etiology. To develop FSHD, D4Z4 contraction needs to occur on a specific genetic background. Only contractions associated with the 4qA161 haplotype cause FSHD. In addition, contraction of the D4Z4 repeat in FSHD patients is associated with significant D4Z4 hypomethylation. To date, however, the methylation status of contracted repeats on nonpathogenic haplotypes has not been studied. We have performed a detailed methylation study of the D4Z4 repeat on chromosome 4q and on a highly homologous repeat on chromosome 10q. We show that patients with a D4Z4 deletion (FSHD1) have D4Z4‐restricted hypomethylation. Importantly, controls with a D4Z4 contraction on a nonpathogenic chromosome 4q haplotype or on chromosome 10q also demonstrate hypomethylation. In 15 FSHD families without D4Z4 contractions but with at least one 4qA161 haplotype (FSHD2), we observed D4Z4‐restricted hypomethylation on chromosomes 4q and 10q. This finding implies that a genetic defect resulting in D4Z4 hypomethylation underlies FSHD2. In conclusion, we describe two ways to develop FSHD: (1) contraction‐dependent or (2) contraction‐independent D4Z4 hypomethylation on the 4qA161 subtelomere. Hum Mutat 30:1–11, 2009. © 2009 Wiley‐Liss, Inc.     

Genetic and Epigenetic Analysis of Recurrent Hydatidiform Mole

Familial biparental hydatidiform mole (FBHM) is a maternal‐effect autosomal recessive disorder in which recurrent pregnancy failure with molar degeneration occurs. The phenotype mimics molar pregnancy due to androgenesis, despite the normal genetic makeup of the conceptus. FBHM appears to result from a failure to establish correct maternal epigenetic identity at imprinted loci during oogenesis. Several women affected with FBHM have previously been shown to have biallelic mutations in the NLRP7 gene (NALP7). Here, we present the results of epigenetic and mutational analysis on FBHM patients from 11 families, 10 of them novel. We demonstrate a methylation defect at imprinted loci in tissue from four new FBHM cases. Biallelic NLRP7 mutations, including eight previously undescribed mutations, were found in all but one family. These results indicate for the first time that maternal imprints at some loci may be correctly specified in FBHM conceptions, since differential methylation of SGCE/PEG10 was preserved in all four cases. © 2009 Wiley‐Liss, Inc.     

Molecular pathological approaches to human tumor immunology

Research on human tumor immunology has greatly advanced in the past two decades. Many immunogenic tumor antigens have been identified, and some of these antigens entered in clinical trials. Consequently, it has been shown that these antigens can inhibit tumor growth in patients to some extent, indicating that they act as potent immunogenic therapeutic vaccines in cancer patients with malignancies originating from various tissues. These patients had antigen‐specific cytotoxic T‐lymphocyte (CTL) responses when assessed on tetramer, enzyme‐linked immunospot (ELISPOT), T‐cell clonotype and CTL induction efficiency. Thus, it has become clear that human tumor vaccines can evoke clinical and immunological anti‐tumor responses in patients. The tumor regression effects of tumor vaccines, however, are generally low, and it is obvious that current vaccination protocols are generally too weak to provide substantial and satisfactory clinical benefits. This means that other drastic and more potent clinical and immunological protocols are required in cancer immunotherapy. To find such efficient protocols the basic immunological and biological properties of cancers must be investigated. In the present review the identification of human tumor antigens recognized on CTL and the clinical trials are introduced. Next, the most recent analysis of human cancer‐initiating cell (cancer stem cell)‐associated antigens is described. These antigens might be able to act as ‘universal, general and fundamental’ tumor antigens. Also present is the authors' recent study for increasing cross‐presentation efficiency in dendritic cells and subsequent enhancement of human leukocyte antigen (HLA)‐class I‐restricted peptide antigenicity by using HSP90 and ORP150 molecular chaperones that act as endogenous Toll‐like receptor ligands. In addition to the aforementioned manipulation of the positive loop of tumor immunity, it is necessary to regulate and intervene in the negative loop. In particular, the potential of the expression of HLA class I molecule regulation by epigenetic mechanisms will be discussed. Finally, the type of basic and clinical tumor immunology research highly required currently, and in the very near future, are described.     

长非编码RNA与其他表观遗传机制在肿瘤中的相互调控

长非编码RNA(lncRNA)是新发现的RNA干扰方式,与其他包括DNA甲基化、组蛋白修饰、染色质重构等表观遗传形式一样,在恶性肿瘤的发生和发展中起着重要作用。近年分子肿瘤学研究显示,lncRNA与其他表观遗传形式相互作用,如lncRNA可通过多种途径调控DNA甲基化、组蛋白修饰、染色质重构和其他RNA干扰形式,而DNA甲基化、染色质重构等也可调控lncRNA的表达及作用;其错综复杂的网路关系影响肿瘤的发生和发展。     

Cellular and epigenetic features of a young healthy and a young osteoarthritic cartilage compared with aged control and OA cartilage

Osteoarthritis (OA) is generally a disease of the elderly population, but can occur in young patients in exceptional cases. This study compares the cellular and epigenetic features of primary old‐age OA with those of secondary OA in a 23‐year‐old patient with developmental dysplasia of the hip. In addition, control cartilage from a 14‐year‐old was compared with that from patients with a fracture of the neck of femur (#NOF) to establish to what extent the latter is a useful control for OA. Articular cartilage was obtained from discarded femoral heads after hip arthroplasty. MMP‐3, MMP‐9, MMP‐13, and ADAMTS‐4 were immunolocalized and the methylation status of specific promoter CpG sites was determined. Both primary and secondary OA were characterized by loss of aggrecan, formation of clones, and abnormal expression of the proteases that correlated with epigenetic DNA demethylation. The latter indicated that the abnormal expression of the cartilage‐degrading proteases was not due to a short‐term up‐regulation, but a heritable, permanent alteration in gene expression. Comparing cell densities in young and old control cartilage estimated an age‐related cell loss of ∼1% per year. In aged #NOF cartilage, some superficial‐zone chondrocytes expressed the proteases, but the majority of cells were immunonegative and their promoters were hypermethylated. The cellular and epigenetic features of the intermediate and deep zones of #NOF cartilage are thus similar to those of young healthy cartilage, justifying the use of #NOF cartilage as control cartilage for OA, providing the superficial zone is removed. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 593–601, 2009