Interplay Between BALL and CREB Binding Protein Maintains H3K27 Acetylation on Active Genes in Drosophila

CREB binding protein (CBP) is a multifunctional transcriptional co-activator that interacts with a variety of transcription factors and acts as a histone acetyltransferase. In Drosophila, CBP mediated acetylation of histone H3 lysine 27 (H3K27ac) is a known hallmark of gene activation regulated by trithorax group proteins (trxG). Recently, we have shown that a histone kinase Ballchen (BALL) substantially co-localizes with H3K27ac at trxG target loci and is required to maintain gene activation in Drosophila. Here, we report a previously unknown interaction between BALL and CBP, which positively regulates H3K27ac. Analysis of genome-wide binding profile of BALL and CBP reveals major overlap and their co-localization at actively transcribed genes. We show that BALL biochemically interacts with CBP and depletion of BALL results in drastic reduction in H3K27ac. Together, these results demonstrate a previously unknown synergy between BALL and CBP and reveals a potentially new pathway required to maintain gene activation during development.

Interplay between BALL and CBP maintains H3K27 acetylation on active genes in Drosophila

CREB binding protein (CBP) is a multifunctional transcriptional co-activator that interacts with a variety of transcription factors and acts as a histone acetyltransferase. In Drosophila, CBP mediated acetylation of histone H3 lysine 27 (H3K27ac) is a known hallmark of gene activation regulated by trithorax group proteins (trxG). Recently, we have shown that a histone kinase Ballchen (BALL) substantially co-localizes with H3K27ac at trxG target loci and is required to maintain gene activation in Drosophila. Here, we report direct interaction between BALL and CBP, which positively regulates H3K27ac. Analysis of genome-wide binding profile of BALL and CBP reveals major overlap and their co-localization at actively transcribed genes. We show that BALL biochemically interacts with CBP and depletion of BALL results in drastic reduction in H3K27ac. Together, these results demonstrate a previously unknown synergy between BALL and CBP and reveals a potentially new pathway required to maintain gene activation during development.

Polycomb and Trithorax Group Proteins: The Long Road from Mutations in Drosophila to Use in Medicine

Polycomb group (PcG) and Trithorax group (TrxG) proteins are evolutionarily conserved factors responsible for the repression and activation of the transcription of multiple genes in Drosophila and mammals. Disruption of the PcG/TrxG expression is associated with many pathological conditions, including cancer, which makes them suitable targets for diagnosis and therapy in medicine. In this review, we focus on the major PcG and TrxG complexes, the mechanisms of PcG/TrxG action, and their recruitment to chromatin. We discuss the alterations associated with the dysfunction of a number of factors of these groups in oncology and the current strategies used to develop drugs based on small-molecule inhibitors.

The Polycomb group methyltransferase StE(z)2 and deposition of H3K27me3 and H3K4me3 regulate the expression of tuberization genes in potato

Polycomb repressive complex (PRC) group proteins regulate various developmental processes in plants by repressing target genes via H3K27 trimethylation, and they function antagonistically with H3K4 trimethylation mediated by Trithorax group proteins. Tuberization in potato has been widely studied, but the role of histone modifications in this process is unknown. Recently, we showed that overexpression of StMSI1, a PRC2 member, alters the expression of tuberization genes in potato. As MSI1 lacks histone-modification activity, we hypothesized that this altered expression could be caused by another PRC2 member, StE(z)2, a potential H3K27 methyltransferase in potato. Here, we demonstrate that a short-day photoperiod influences StE(z)2 expression in the leaves and stolons. StE(z)2 overexpression alters plant architecture and reduces tuber yield, whereas its knockdown enhances yield. ChIP-sequencing using stolons induced by short-days indicated that several genes related to tuberization and phytohormones, such as StBEL5/11/29, StSWEET11B, StGA2OX1, and StPIN1 carry H3K4me3 or H3K27me3 marks and/or are StE(z)2 targets. Interestingly, we observed that another important tuberization gene, StSP6A, is targeted by StE(z)2 in leaves and that it has increased deposition of H3K27me3 under long-day (non-induced) conditions compared to short days. Overall, our results show that StE(z)2 and deposition of H3K27me3 and/or H3K4me3 marks might regulate the expression of key tuberization genes in potato.

A theoretical model of Polycomb/Trithorax action unites stable epigenetic memory and dynamic regulation

Polycomb and Trithorax group proteins maintain stable epigenetic memory of gene expression states for some genes, but many targets show highly dynamic regulation. Here we combine experiment and theory to examine the mechanistic basis of these different modes of regulation. We present a mathematical model comprising a Polycomb/Trithorax response element (PRE/TRE) coupled to a promoter and including Drosophila developmental timing. The model accurately recapitulates published studies of PRE/TRE mediated epigenetic memory of both silencing and activation. With minimal parameter changes, the same model can also recapitulate experimental data for a different PRE/TRE that allows dynamic regulation of its target gene. The model predicts that both cell cycle length and PRE/TRE identity are critical for determining whether the system gives stable memory or dynamic regulation. Our work provides a simple unifying framework for a rich repertoire of PRE/TRE functions, and thus provides insights into genome-wide Polycomb/Trithorax regulation.

Genome-wide Prediction of Potential Polycomb Response Elements and their Functions

The Polycomb-group proteins (PcG) and Trithorax-group proteins (TrxG) are two major epigenetic regulators important for proper differentiation during development (1, 2). In Drosophila melanogaster (D. melanogaster), Polycomb response elements (PREs) are short segments of DNA with a high density of binding sites for transcription factors (TFs) that recruit PcG and TrxG proteins to chromatin. Each PRE has a different number of binding sites for PcG and TrxG, and these binding sites have different topological organizations. It is thus difficult to find general rules to discover the locations of PREs over the entire genome. We have developed a framework to predict the locations and roles of potential PRE regions over the entire D. melanogaster genome using machine learning algorithms. Using a combination of motif-based and simple sequence-based features, we were able to train a random forest (RF) model with very high performance in predicting active PRE regions. This model could distinguish potential PRE regions from non-PRE regions (precision and recall ~0.92 upon cross-validation). In the process, the model suggests that previously unrecognized TFs might contribute to PcG/TrxG recruitment at the PRE locations, as the presence of binding sites for those factors is strongly informative of active PREs. A secondary regression model provides information on features that further differentiate PREs into functional subclasses. Our findings provide both new predictions of 7887 potential PREs in the D. melanogaster genome, and new mechanistic insight into the set of DNA-associated proteins that may contribute to PcG recruitment and/or activity.

Chromatin modulation and gene regulation in plants: insight about PRC1 function

In plant and metazoan, Polycomb Group (PcG) proteins play key roles in regulating developmental processes by repression of gene expression. PcG proteins function as multi-protein complexes; among them the best characterized ones are Polycomb Repressive Complex 1 (PRC1) and PRC2. PRC2 catalyzes histone H3 lysine 27 trimethylation (H3K27me3), and PRC1 can bind H3K27me3 and catalyzes H2A monoubiquitination. While the PRC2 components and molecular functions are evolutionarily conserved, varied PRC1 complexes are found and they show high divergences between animals and plants. In addition to the core subunits, an exponentially increasing number of PRC1-associated factors have been identified in Arabidopsis thaliana. Recent studies have also unraveled cross-component interactions and intertwined roles of PRC1 and PRC2 in chromatin modulation. In addition, complexities of interactions and functions between PcG and Trithorax Group proteins have been observed. This short review summarizes up current knowledge to provide insight about repressive functional mechanism of PRC1 and its interplay with other factors.