Characterization of genome-wide enhancer-promoter interactions reveals co-expression of interacting genes and modes of higher order chromatin organization

Recent epigenomic studies have predicted thousands of potential enhancers in the human genome. However, there has not been systematic characterization of target promoters for these potential enhancers. Using H3K4me2 as a mark for active enhancers, we identified genome-wide EP interactions in human CD4⁺ T cells. Among the 6 520 long-distance chromatin interactions, we identify 2 067 enhancers that interact with 1 619 promoters and enhance their expression. These enhancers exist in accessible chromatin regions and are associated with various histone modifications and polymerase II binding. The promoters with interacting enhancers are expressed at higher levels than those without interacting enhancers, and their expression levels are positively correlated with the number of interacting enhancers. Interestingly, interacting promoters are co-expressed in a tissue-specific manner. We also find that chromosomes are organized into multiple levels of interacting domains. Our results define a global view of EP interactions and provide a data set to further understand mechanisms of enhancer targeting and long-range chromatin organization. The Gene Expression Omnibus accession number for the raw and analyzed chromatin interaction data is {"type":"entrez-geo","attrs":{"text":"GSE32677","term_id":"32677"}}GSE32677.     

Dynamics of H3K27me3 methylation and demethylation in plant development

Epigenetic regulation controls multiple aspects of the plant development. The N-terminal tail of histone can be differently modified to regulate various chromatin activities. One of them, the trimethylation of histone H3 lysine 27 (H3K27me3) confers a repressive chromatin state with gene silencing. H3K27me3 is dynamically deposited and removed throughout development. While components of the H3K27me3 writer, Polycomb repressive complex 2 (PRC2), have been reported for almost 2 decades, it is only recently that JUMONJI (JMJ) proteins are reported as H3K27me3 demethylases, affirming the dynamic nature of histone modifications. This review highlights recent progress in plant epigenetic research, focusing on the H3K27me3 demethylases.     

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.     

Broad Chromatin Domains: An Important Facet of Genome Regulation

Chromatin composition differs across the genome, with distinct compositions characterizing regions associated with different properties and functions. Whereas many histone modifications show local enrichment over genes or regulatory elements, marking can also span large genomic intervals defining broad chromatin domains. Here we highlight structural and functional features of chromatin domains marked by histone modifications, with a particular emphasis on the potential roles of H3K27 methylation domains in the organization and regulation of genome activity in metazoans.     

组蛋白变体H3.3 L27M突变与胶质瘤发生

组蛋白变体在基因表达等基本细胞过程中发挥重要调节功能。人类有5种H3变体,分别为H3.1、 H3.2、H3.3、着丝粒特异性CENP-A和睾丸特异性H3t。人H3.3有H3F3A和H3F3B两个基因编码。采用DNA全基因组测序的方法在儿童高级别胶质瘤如恶性胶质瘤（GBM）和弥漫性内在脑桥胶质瘤（DIPG）鉴定出高频的H3F3A突变。超过70%DIPG和30%GBM携带H3.3 K27M氨基酸错义突变（27位赖氨酸被甲硫氨酸代替）。H3.3 K27M通过与组蛋白H3K27甲基转移酶EZH2亚基相互作用而抑制多梳抑制复合物2（PRC2）活性并全面减少H3K27me3含量。因此H3.3 K27M突变重塑了表观修饰状态和基因表达模式,从而驱动肿瘤发生。K27M突变可作为分子标志物以更好区分儿童胶质瘤亚型,还可作为特异、敏感的预后标志物。通过抑制组蛋白去甲基化酶如JMJD3活性而增加H3K27甲基化可作为K27M突变胶质瘤治疗的有效策略。本文综述了组蛋白变体H3.3 K27M在胶质瘤中的突变模式、分子机制和临床应用。     

DeepCAPE: A Deep Convolutional Neural Network for the Accurate Prediction of Enhancers

The establishment of a landscape of enhancers across human cells is crucial to deciphering the mechanism of gene regulation, cell differentiation, and disease development. High-throughput experimental approaches, which contain successfully reported enhancers in typical cell lines, are still too costly and time-consuming to perform systematic identification of enhancers specific to different cell lines. Existing computational methods, capable of predicting regulatory elements purely relying on DNA sequences, lack the power of cell line-specific screening. Recent studies have suggested that chromatin accessibility of a DNA segment is closely related to its potential function in regulation, and thus may provide useful information in identifying regulatory elements. Motivated by the aforementioned understanding, we integrate DNA sequences and chromatin accessibility data to accurately predict enhancers in a cell line-specific manner. We proposed DeepCAPE, a deep convolutional neural network to predict enhancers via the integration of DNA sequences and DNase-seq data. Benefitting from the well-designed feature extraction mechanism and skip connection strategy, our model not only consistently outperforms existing methods in the imbalanced classification of cell line-specific enhancers against background sequences, but also has the ability to self-adapt to different sizes of datasets. Besides, with the adoption of auto-encoder, our model is capable of making cross-cell line predictions. We further visualize kernels of the first convolutional layer and show the match of identified sequence signatures and known motifs. We finally demonstrate the potential ability of our model to explain functional implications of putative disease-associated genetic variants and discriminate disease-related enhancers. The source code and detailed tutorial of DeepCAPE are freely available at https://github.com/ShengquanChen/DeepCAPE.     

组蛋白去甲基酶UTX在发育和疾病中的作用

UTX(ubiquitously transcribed tetratricopeptide repeat,X chromosome)是抑制性组蛋白H3K27me3的特异性去甲基化酶,和甲基转移酶PRC2共同调控H3K27me3。此外,UTX也是组蛋白H3K4甲基转移酶MLL3/MLL4的组成部分。UTX参与胚胎发育、HOX基因的表达和重编程等生命过程。在歌舞伎综合征中,UTX突变是关键的致病因素。同时,UTX作为肿瘤抑制因子参与多种实体肿瘤和血液肿瘤的产生。该文总结了UTX在正常发育和疾病发生中的作用及近期研究的重大突破,并结合我们的研究探讨了UTX对体细胞重编程的影响。