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

An Integrated Computational Materials Engineering Predictive Platform for Fatigue Prediction and Qualification of Metallic Parts Built With Additive Manufacturing

Abstract Additive manufacturing (AM) processes create material directly into a functional shape. Often the material properties vary with part geometry, orientation, and build layout. Today, trial-and-error methods are used to generate material property data under controlled conditions that may not map to the entire range of geometries over a part. Described here is the development of a modeling tool enabling prediction of the performance of parts built with AM, with rigorous consideration of the microstructural properties governing the nucleation and propagation of fatigue cracks. This tool, called DigitalClone® for additive manufacturing (DCAM), is an Integrated Computational Materials Engineering (ICME) tool that includes models of crack initiation and damage progression with the high-fidelity process and microstructure modeling approaches. The predictive model has three main modules: process modeling, microstructure modeling, and fatigue modeling. In this paper, a detailed description and theoretical basis of each module is provided. Experimental validations (microstructure, porosity, and fatigue) of the tool using multiple material characterization and experimental coupon testing for five different AM materials are discussed. The physics-based computational modeling encompassed within DCAM provides an efficient capability to fully explore the design space across geometries and materials, leading to components that represent the optimal combination of performance, reliability, and durability.</jats:p

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

ABSTRACTIn nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The DNA-bound 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 engagement of H3K4me3 by the BPTF PHD finger, but it is unknown if this mechanism has broader extension. Here we show that cis H3 tail acetylation promotes nucleosomal accessibility to other H3K4 methyl readers, and importantly, extends to H3K4 writers, notably methyltransferase MLL1. This regulation is nucleosome-dependent and also observed in vivo, where H3 acetylation is directly linked to increased levels of H3K4 methylation on the same histone tail. These observations reveal an acetylation ‘chromatin switch’ on the H3 tail that modulates the accessibility and function of H3K4 methylation in chromatin. Our findings also resolve the long-standing question of why H3K4me3 levels are coupled with H3 acetylation.</jats:p

Nucleosome conformation dictates the histone code

Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized ‘codes’ that are read by specialized regions (reader domains) in chromatin-associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP: histone PTM] specificities, and thus decipher the histone code and guide epigenetic therapies. However, this has largely been done using the reductive approach of isolated reader domains and histone peptides, which cannot account for any higher-order factors. Here, we show that the [BPTF PHD finger and bromodomain: histone PTM] interaction is dependent on nucleosome context. The tandem reader selectively associates with nucleosomal H3K4me3 and H3K14ac or H3K18ac, a combinatorial engagement that despite being in cis is not predicted by peptides. This in vitro specificity of the BPTF tandem reader for PTM-defined nucleosomes is recapitulated in a cellular context. We propose that regulatable histone tail accessibility and its impact on the binding potential of reader domains necessitates we refine the ‘histone code’ concept and interrogate it at the nucleosome level