Tetraarsenic oxide affects non-coding RNA transcriptome through deregulating polycomb complexes in MCF7 cells.

Non-coding RNAs (ncRNAs) play important and diverse roles in mammalian cell biology and pathology. Although the functions of an increasing number of ncRNAs have been identified, the mechanisms underlying ncRNA gene expression remain elusive and are incompletely understood. Here, we investigated ncRNA gene expression in Michigan cancer foundation 7 (MCF7), a malignant breast cancer cell line, on treatment of tetraarsenic oxide (TAO), a potential anti-cancer drug. Our genomic analyses found that TAO up- or down-regulated ncRNA genes genome-wide. A subset of identified ncRNAs with critical biological and clinical functions were validated by real-time quantitative polymerase chain reaction. Intriguingly, these TAO-regulated genes included CDKN2B-AS, HOXA11-AS, SHH, and DUSP5 that are known to interact with or be targeted by polycomb repressive complexes (PRCs). In addition, the PRC subunits were enriched in these TAO-regulated ncRNA genes and TAO treatment deregulated the expression of PRC subunits. Strikingly, TAO decreased the cellular and gene-specific levels of EZH2 expression and H3K27me3. In particular, TAO reduced EZH2 and H3K27me3 and increased transcription at MALAT1 gene. Inhibiting the catalytic activity of EZH2 using GSK343 increased representative TAO-inducible ncRNA genes. Together, our findings suggest that the expression of a subset of ncRNA genes is regulated by PRC2 and that TAO could be a potent epigenetic regulator through PRCs to modulate the ncRNA gene expression in MCF7 cells.

Dynamic Competition of Polycomb and Trithorax in Transcriptional Programming.

Predicting regulatory potential from primary DNA sequences or transcription factor binding patterns is not possible. However, the annotation of the genome by chromatin proteins, histone modifications, and differential compaction is largely sufficient to reveal the locations of genes and their differential activity states. The Polycomb Group (PcG) and Trithorax Group (TrxG) proteins are the central players in this cell type-specific chromatin organization. PcG function was originally viewed as being solely repressive and irreversible, as observed at the homeotic loci in flies and mammals. However, it is now clear that modular and reversible PcG function is essential at most developmental genes. Focusing mainly on recent advances, we review evidence for how PcG and TrxG patterns change dynamically during cell type transitions. The ability to implement cell type-specific transcriptional programming with exquisite fidelity is essential for normal development.

Polycomb complexes in normal and malignant hematopoiesis.

Epigenetic mechanisms are crucial for sustaining cell type-specific transcription programs. Among the distinct factors, Polycomb group (PcG) proteins are major negative regulators of gene expression in mammals. These proteins play key roles in regulating the proliferation, self-renewal, and differentiation of stem cells. During hematopoietic differentiation, many PcG proteins are fundamental for proper lineage commitment, as highlighted by the fact that a lack of distinct PcG proteins results in embryonic lethality accompanied by differentiation biases. Correspondingly, proteins of these complexes are frequently dysregulated in hematological diseases. In this review, we present an overview of the role of PcG proteins in normal and malignant hematopoiesis, focusing on the compositional complexity of PcG complexes, and we briefly discuss the ongoing clinical trials for drugs targeting these factors.

The dynamic interactome and genomic targets of Polycomb complexes during stem-cell differentiation.

Although the core subunits of Polycomb group (PcG) complexes are well characterized, little is known about the dynamics of these protein complexes during cellular differentiation. We used quantitative interaction proteomics and genome-wide profiling to study PcG proteins in mouse embryonic stem cells (ESCs) and neural progenitor cells (NPCs). We found that the stoichiometry and genome-wide binding of PRC1 and PRC2 were highly dynamic during neural differentiation. Intriguingly, we observed a downregulation and loss of PRC2 from chromatin marked with trimethylated histone H3 K27 (H3K27me3) during differentiation, whereas PRC1 was retained at these sites. Additionally, we found PRC1 at enhancer and promoter regions independently of PRC2 binding and H3K27me3. Finally, overexpression of NPC-specific PRC1 interactors in ESCs led to increased Ring1b binding to, and decreased expression of, NPC-enriched Ring1b-target genes. In summary, our integrative analyses uncovered dynamic PcG subcomplexes and their widespread colocalization with active chromatin marks during differentiation.

Genome-wide identification, classification and expression analysis of the PHD-finger protein family in Populus trichocarpa.

The plant homeobox domain (PHD) proteins are widespread in eukaryotes, and play important roles in regulating chromatin and transcription. Comprehensive analyses of PHD-finger proteins have been performed in animals, but few plant PHD-finger proteins involved in growth and development have been characterized functionally. In this study, we conducted a genome-wide survey of PHD-finger proteins in Populus trichocarpa by describing the phylogenetic relationship, gene structure, and chromosomal location and microarray analyses of each predicted PHD-finger family member. We identified 73 PHD-finger genes (PtPHD1-73) and classified them into eleven subfamilies (A-K) by phylogenetic analysis. Seventy-two of the 73 genes were unevenly distributed on all 19 chromosomes, with seven segmental duplication events. Analysis of the Ka (non-synonymous substitution rate)/Ks (synonymous substitution rate) ratios suggested that the duplicated genes of the PHD-finger family mainly underwent purifying selection with restrictive functional divergence after the duplication events. Expression profiles analysis indicated that 67 PHD-finger genes were differentially expressed in various tissues. Quantitative real-time RT-PCR (qRT-PCR) analyses of nine selected PtPHD genes under high salinity, drought and cold stresses were also performed to explore their stress-related expression patterns. The results of this study provide a thorough overview of poplar PHD-finger proteins and will be valuable for further functional research of poplar PHD-finger genes to unravel their biological roles.

Gene silencing and Polycomb group proteins: an overview of their structure, mechanisms and phylogenetics.

DNA methylation, histone modifications, and chromatin configuration are crucially important in the regulation of gene expression. Among these epigenetic mechanisms, silencing the expression of certain genes depending on developmental stage and tissue specificity is a key repressive system in genome programming. Polycomb (Pc) proteins play roles in gene silencing through different mechanisms. These proteins act in complexes and govern the histone methylation profiles of a large number of genes that regulate various cellular pathways. This review focuses on two main Pc complexes, Pc repressive complexes 1 and 2, and their phylogenetic relationship, structures, and function. The dynamic roles of these complexes in silencing will be discussed herein, with a focus on the recruitment of Pc complexes to target genes and the key factors involved in their recruitment.