Histone H3K18 & H3K23 acetylation directs establishment of MLL-mediated H3K4 methylation.

In an unmodified state, positively charged histone N-terminal tails engage nucleosomal DNA in a manner which restricts access to not only the underlying DNA, but also key tail residues subject to binding and/or modification. Charge-neutralizing modifications, such as histone acetylation, serve to disrupt this DNA-tail interaction, facilitating access to such residues. We previously showed that a polyacetylation-mediated chromatin "switch" governs the read-write capability of H3K4me3 by the MLL1 methyltransferase complex. Here, we discern the relative contributions of site-specific acetylation states along the H3 tail and extend our interrogation to other chromatin modifiers. We show that the contributions of H3 tail acetylation to H3K4 methylation by MLL1 are highly variable, with H3K18 and H3K23 acetylation exhibiting robust stimulatory effects, and that this extends to the related H3K4 methyltransferase complex, MLL4. We show that H3K4me1 and H3K4me3 are found preferentially co-enriched with H3 N-terminal tail proteoforms bearing dual H3K18 and H3K23 acetylation (H3{K18acK23ac}). We further show that this effect is specific to H3K4 methylation, while methyltransferases targeting other H3 tail residues (H3K9, H3K27, & H3K36), a methyltransferase targeting the nucleosome core (H3K79), and a kinase targeting a residue directly adjacent to H3K4 (H3T3) are insensitive to tail acetylation. Together, these findings indicate a unique and robust stimulation of H3K4 methylation by H3K18 and H3K23 acetylation and provide key insight into why H3K4 methylation is often associated with histone acetylation in the context of active gene expression.

H3K18 & H3K23 acetylation directs establishment of MLL-mediated H3K4 methylation.

In an unmodified state, positively charged histone N-terminal tails engage nucleosomal DNA in a manner which restricts access to not only the underlying DNA, but also key tail residues subject to binding and/or modification. Charge-neutralizing modifications, such as histone acetylation, serve to disrupt this DNA-tail interaction, facilitating access to such residues. We previously showed that a polyacetylation-mediated chromatin "switch" governs the read-write capability of H3K4me3 by the MLL1 methyltransferase complex. Here, we discern the relative contributions of site-specific acetylation states along the H3 tail and extend our interrogation to other chromatin modifiers. We show that the contributions of H3 tail acetylation to H3K4 methylation by MLL1 are highly variable, with H3K18 and H3K23 acetylation exhibiting robust stimulatory effects, and that this extends to the related H3K4 methyltransferase complex, MLL4. We show that H3K4me1 and H3K4me3 are found preferentially co-enriched with H3 N-terminal tail proteoforms bearing dual H3K18 and H3K23 acetylation (H3{K18acK23ac}). We further show that this effect is specific to H3K4 methylation, while methyltransferases targeting other H3 tail residues (H3K9, H3K27, & H3K36), a methyltransferase targeting the nucleosome core (H3K79), and a kinase targeting a residue directly adjacent to H3K4 (H3T3) are insensitive to tail acetylation. Together, these findings indicate a unique and robust stimulation of H3K4 methylation by H3K18 and H3K23 acetylation and provide key insight into why H3K4 methylation is often associated with histone acetylation in the context of active gene expression.

An acetylation-mediated chromatin switch governs H3K4 methylation read-write capability.

In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The latter state is expected to impact histone N-termini availability to the epigenetic machinery. Notably, H3 tail acetylation (e.g. K9ac, K14ac, K18ac) is linked to increased H3K4me3 engagement by the BPTF PHD finger, but it is unknown if this mechanism has a broader extension. Here, we show that H3 tail acetylation promotes nucleosomal accessibility to other H3K4 methyl readers, and importantly, extends to H3K4 writers, notably methyltransferase MLL1. This regulation is not observed on peptide substrates yet occurs on the cis H3 tail, as determined with fully-defined heterotypic nucleosomes. In vivo, H3 tail acetylation is directly and dynamically coupled with cis H3K4 methylation levels. Together, these observations reveal an acetylation 'chromatin switch' on the H3 tail that modulates read-write accessibility in nucleosomes and resolves the long-standing question of why H3K4me3 levels are coupled with H3 acetylation.

MGEScan: a Galaxy-based system for identifying retrotransposons in genomes.

UNLABELLED: : MGEScan-long terminal repeat (LTR) and MGEScan-non-LTR are successfully used programs for identifying LTRs and non-LTR retrotransposons in eukaryotic genome sequences. However, these programs are not supported by easy-to-use interfaces nor well suited for data visualization in general data formats. Here, we present MGEScan, a user-friendly system that combines these two programs with a Galaxy workflow system accelerated with MPI and Python threading on compute clusters. MGEScan and Galaxy empower researchers to identify transposable elements in a graphical user interface with ready-to-use workflows. MGEScan also visualizes the custom annotation tracks for mobile genetic elements in public genome browsers. A maximum speed-up of 3.26× is attained for execution time using concurrent processing and MPI on four virtual cores. MGEScan provides four operational modes: as a command line tool, as a Galaxy Toolshed, on a Galaxy-based web server, and on a virtual cluster on the Amazon cloud. AVAILABILITY AND IMPLEMENTATION: MGEScan tutorials and source code are available at http://mgescan.readthedocs.org/ CONTACT: hatang@indiana.edu or syoh@ajou.ac.kr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Improving usability and accessibility of cheminformatics tools for chemists through cyberinfrastructure and education.

Some of the latest trends in cheminformatics, computation, and the world wide web are reviewed with predictions of how these are likely to impact the field of cheminformatics in the next five years. The vision and some of the work of the Chemical Informatics and Cyberinfrastructure Collaboratory at Indiana University are described, which we base around the core concepts of e-Science and cyberinfrastructure that have proven successful in other fields. Our chemical informatics cyberinfrastructure is realized by building a flexible, generic infrastructure for cheminformatics tools and databases, exporting "best of breed" methods as easily-accessible web APIs for cheminformaticians, scientists, and researchers in other disciplines, and hosting a unique chemical informatics education program aimed at scientists and cheminformatics practitioners in academia and industry.

Web service infrastructure for chemoinformatics.

The vast increase of pertinent information available to drug discovery scientists means that there is a strong demand for tools and techniques for organizing and intelligently mining this information for manageable human consumption. At Indiana University, we have developed an infrastructure of chemoinformatics Web services that simplifies the access to this information and the computational techniques that can be applied to it. In this paper, we describe this infrastructure, give some examples of its use, and then discuss our plans to use it as a platform for chemoinformatics application development in the future.