Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries

Recent advances in stem cell biology have shed light on how normal stem and progenitor cells can evolve to acquire malignant characteristics during tumorigenesis. The cancer counterparts of normal stem and progenitor cells might be occurred through alterations of stem cell fates including an increase in self-renewal capability and a decrease in differentiation and/or apoptosis. This oncogenic evolution of cancer stem and progenitor cells, which often associates with aggressive phenotypes of the tumorigenic cells, is controlled in part by dysregulated epigenetic mechanisms including aberrant DNA methylation leading to abnormal epigenetic memory. Epigenetic therapy by targeting DNA methyltransferases(DNMT) 1, DNMT3 A and DNMT3 B via 5-Azacytidine(Aza) and 5-Aza-2'-deoxycytidine(Aza-d C) has proved to be successfultoward treatment of hematologic neoplasms especially for patients with myelodysplastic syndrome. In this review, I summarize the current knowledge of mechanisms underlying the inhibition of DNA methylation by Aza andAza-d C, and of their apoptotic- and differentiation-inducingeffects on cancer stem and progenitor cells in leukemia, medulloblastoma, glioblastoma, neuroblastoma, prostate cancer, pancreatic cancer and testicular germ cell tumors. Since cancer stem and progenitor cells are implicatedin cancer aggressiveness such as tumor formation, progression, metastasis and recurrence, I propose that effective therapeutic strategies might be achievedthrough eradication of cancer stem and progenitor cells by targeting the DNA methylation machineries to interfere their "malignant memory".

Medical Radiation Exposure and Human Carcinogenesis-Genetic and Epigenetic Mechanisms

Ionizing radiation （IR） is a potential carcinogen. Evidence for the carcinogenic effect of IR radiation has been shown after long-term animal investigations and observations on survivors of the atom bombs in Hiroshima and Nagasaki. However, IR has been widely used in a controlled manner in the medical imaging for diagnosis and monitoring of various diseases and also in cancer therapy. The collective radiation dose from medical imagings has increased six times in the last two decades, and grow continuously day to day. A large number of evidence has revealed the increased cancer risk in the people who had frequently exposed to x-rays, especially in childhood. It has also been shown that secondary malignancy may develop within the five years in cancer survivors who have received radiotherapv, because of IR-mediated damage to healthy cells. In this article, we review the current knowledge about the role of medical x-ray exposure in cancer development in humans, and recently recognized epigenetic mechanisms in IR-induced carcinogenesis.

DNA Methylation and Birth Weight: a Genome-wide Analysis

The study illustrate the inner correlation between global DNA methylation variation and different birth weights. Infant birth weight was used to identify cases and controls. Cord blood and placentas were collected. We performed DNA methylation profiling of bisulphite‐converted DNA. We have identified many differentially methylated Cp G sites in experimental groups; these sites involved in hundreds of signalings. Among these, more than ten pathways were referred to the glucose and lipid metabolism. Methylation changes in the insulin‐signaling pathway（ISP）, adipocytokine signaling pathway（ASP） and MAPK signaling pathway are involved in the fetal programming of diabetes.

The transgenerational effects of maternal low-protein diet during lactation on offspring

Environmental factors such as diet and lifestyle can influence the health of both mothers and offspring.However,its transgenerational transmission and underlying mechanisms remain largely unknown.Here,using a maternal lactation-period low-protein diet(LPD)mouse model,we show that maternal LPD during lactation causes decreased survival and stunted growth,significantly reduces ovulation and litter size,and alters the gut microbiome in the female LPD-F1 offspring.The transcriptome of LPD-F1 metaphase II(MII)oocytes shows that differentially expressed genes are enriched in female pregnancy and multiple metabolic processes.Moreover,maternal LPD causes early stunted growth and impairs metabolic health,which is transmitted over two generations.The methylome alteration of LPD-F1 oocytes can be partly transmitted to the F2 oocytes.Together,our results reveal that LPD during lactation transgenerationally affects offspring health,probably via oocyte epigenetic changes.

Two imprinted genes primed by DEMETER in the central cell and activated by WRKY10 in the endosperm

The early development of the endosperm is crucial for balancing the allocation of maternal nutrients to offspring.This process is believed to be evolutionarily associated with genomic imprinting,resulting in parentally biased allelic gene expression.Beyond Fertilization Independent Seed(FIS)genes,the number of imprinted genes involved in early endosperm development and seed size determination remains limited.This study introduces early endosperm-expressed HAIKU(IKU)downstream Candidate F-box 1(ICF1)and ICF2 as maternally expressed imprinted genes(MEGs)in Arabidopsis thaliana.Although these genes are also demethylated by DEMETER(DME)in the central cell,their activation differs from the direct DME-mediated activation seen in classical MEGs such as the FIS genes.Instead,ICF maternal alleles carry pre-established hypomethylation in their promoters,priming them for activation by the WRKY10 transcription factor in the endosperm.On the contrary,paternal alleles are predominantly suppressed by CG methylation.Furthermore,we find that ICF genes partially contribute to the small seed size observed in iku mutants.Our discovery reveals a two-step regulatory mechanism that highlights the important role of conventional transcription factors in the activation of imprinted genes,which was previously not fully recognized.Therefore,the mechanism provides a new dimension to understand the transcriptional regulation of imprinting in plant reproduction and development.

Non-coding RNAs and Their Roles in Stress Response in Plants

Eukaryotic genomes encode thousands of non-coding RNAs （ncRNAs）, which play cru- cial roles in transcriptional and post-transcriptional regulation of gene expression. Accumulating evidence indicates that ncRNAs, especially microRNAs （miRNAs） and long ncRNAs （lncRNAs）, have emerged as key regulatory molecules in plant stress responses. In this review, we have summa- rized the current progress on the understanding of plant miRNA and incRNA identification, characteristics, bioinformatics tools, and resources, and provided examples of mechanisms of miRNA- and lncRNA-mediated plant stress tolerance.

Genome-wide DNA methylation variations upon engineered nanomaterials and their implications in nanosafety assessment

Subject Code:B07With the support by the National Natural Science Foundation of China,the National'973'Program,and the Strategic Priority Research Program of the Chinese Academy of Sciences,the research team led by Prof.Liu Sijin(刘思金)at the State Key Laboratory of Environmental Chemistry and Ecotoxicology,Research Center for Eco-Environmental Sciences,Chinese Academy of Sciences,uncovered the