Maternal and paternal alleles exhibit differential histone methylation and acetylation at maize imprinted genes

Imprinting is an epigenetically controlled form of gene regulation in which the expression of a gene is based on its parent of origin. This epigenetic regulation is likely to involve allele-specific DNA or histone modifications. The relative abundance of eight different histone modifications was tested at various regions in several imprinted maize (Zea mays) genes using a chromatin immunoprecipitation protocol coupled with quantitative allele-specific single nucleotide polymorphism assays. Histone H3 lysine-27 di- and tri-methylation are paternally enriched at the imprinted loci Mez1, ZmFie1 and Nrp1. In contrast, acetylation of histones H3 and H4 and H3K4 dimethylation are enriched at the maternal alleles of these genes. Di- and tri-methylation of H3 lysine-9, which is generally associated with constitutively silenced chromatin, was not enriched at either allele of imprinted loci. These patterns of enrichment were specific to tissues that exhibit imprinting. In addition, the enrichment of these modifications was dependent upon the parental origin of an allele and not sequence differences between the alleles, as demonstrated by reciprocal crosses. This study presents a detailed view of the chromatin modifications that are associated with the maternal and paternal alleles at imprinted loci and provides evidence for common histone modifications at multiple imprinted loci.     

Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer

The mechanism of DNA hypermethylation-associated tumor suppressor gene silencing in cancer remains incompletely understood. Here, we show by chromatin immunoprecipitation that for three genes (P16, MLH1, and the O(6)-methylguanine-DNA methyltransferase gene, MGMT), histone H3 Lys-9 methylation directly correlates and histone H3 Lys-9 acetylation inversely correlates with DNA methylation in three neoplastic cell lines. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) resulted in moderately increased Lys-9 acetylation at silenced loci with no effect on Lys-9 methylation and minimal effects on gene expression. By contrast, treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza-dC) rapidly reduced Lys-9 methylation at silenced loci and resulted in reactivation for all three genes. Combined treatment with 5Aza-dC and TSA was synergistic in reactivating gene expression through simultaneous effects on Lys-9 methylation and acetylation, which resulted in a robust increase in the ratio of Lys-9 acetylated and methylated histones at loci showing dense DNA methylation. By contrast to Lys-9, histone H3 Lys-4 methylation inversely correlated with promoter DNA methylation, was not affected by TSA, and was increased moderately at silenced loci by 5Aza-dC. Our results suggest that reduced H3 Lys-4 methylation and increased H3 Lys-9 methylation play a critical role in the maintenance of promoter DNA methylation-associated gene silencing in colorectal cancer.     

“先驱”转录因子LEC1在早期胚胎重置春化状态的机制

开花是植物由营养生长阶段向生殖生长阶段转变的重要过程, 长时间低温处理即春化对开花起到非常重要的促进作用。春化控制的拟南芥(Arabidopsis thaliana)开花中, 阻抑型转录因子FLC是重要的关节点, 春化记忆依赖于对该基因的控制。何跃辉研究组之前对拟南芥的研究揭示了转录因子VAL1或VAL2可以识别负调控开花的关键基因FLC成核区的顺式DNA元件, 协同PRC2复合体在春化过程中沉默FLC基因的表达, 并在随后的常温下继续维持FLC基因沉默直至受精结束, 使植物产生春化记忆。但在下一代中如何擦除这种记忆功能, 使FLC重新被激活, 以防止植物在过冬前或过冬时开花, 相关机制目前并不清楚。近期, 该研究组揭示了在植物胚胎发育早期一个种子特有的“先驱”转录因子参与擦除春化记忆, 重新激活FLC基因的分子机制, 并解析了胚胎中的基因激活传递到后胚胎发育(营养生长期)的表观遗传机理。该研究是开花领域的重要突破, 为作物开花调控的生产应用提供了新思路。