asteRIa enables robust interaction modeling between chromatin modifications and epigenetic readers.

Chromatin, the nucleoprotein complex consisting of DNA and histone proteins, plays a crucial role in regulating gene expression by controlling access to DNA. Chromatin modifications are key players in this regulation, as they help to orchestrate DNA transcription, replication, and repair. These modifications recruit epigenetic 'reader' proteins, which mediate downstream events. Most modifications occur in distinctive combinations within a nucleosome, suggesting that epigenetic information can be encoded in combinatorial chromatin modifications. A detailed understanding of how multiple modifications cooperate in recruiting such proteins has, however, remained largely elusive. Here, we integrate nucleosome affinity purification data with high-throughput quantitative proteomics and hierarchical interaction modeling to estimate combinatorial effects of chromatin modifications on protein recruitment. This is facilitated by the computational workflow asteRIa which combines hierarchical interaction modeling, stability-based model selection, and replicate-consistency checks for a stable estimation of Robust Interactions among chromatin modifications. asteRIa identifies several epigenetic reader candidates responding to specific interactions between chromatin modifications. For the polycomb protein CBX8, we independently validate our results using genome-wide ChIP-Seq and bisulphite sequencing datasets. We provide the first quantitative framework for identifying cooperative effects of chromatin modifications on protein binding.

Decoding chromatin states by proteomic profiling of nucleosome readers.

DNA and histone modifications combine into characteristic patterns that demarcate functional regions of the genome1,2. While many 'readers' of individual modifications have been described3-5, how chromatin states comprising composite modification signatures, histone variants and internucleosomal linker DNA are interpreted is a major open question. Here we use a multidimensional proteomics strategy to systematically examine the interaction of around 2,000 nuclear proteins with over 80 modified dinucleosomes representing promoter, enhancer and heterochromatin states. By deconvoluting complex nucleosome-binding profiles into networks of co-regulated proteins and distinct nucleosomal features driving protein recruitment or exclusion, we show comprehensively how chromatin states are decoded by chromatin readers. We find highly distinctive binding responses to different features, many factors that recognize multiple features, and that nucleosomal modifications and linker DNA operate largely independently in regulating protein binding to chromatin. Our online resource, the Modification Atlas of Regulation by Chromatin States (MARCS), provides in-depth analysis tools to engage with our results and advance the discovery of fundamental principles of genome regulation by chromatin states.

Statistical modeling of dynamic eye-tracking experiments: Relative importance of visual stimulus elements for gaze behavior in the multi-group case.

This paper presents a model that allows group comparisons of gaze behavior while watching dynamic video stimuli. The model is based on the approach of Coutrot and Guyader (2017) and allows linear combinations of feature maps to form a master saliency map. The feature maps in the model are, for example, the dynamically salient contents of a video stimulus or predetermined areas of interest. The model takes into account temporal aspects of the stimuli, which is a crucial difference to other common models. The multi-group extension of the model introduced here allows to obtain relative importance plots, which visualize the effect of a specific feature of a stimulus on the attention and visual behavior for two or more experimental groups. These plots are interpretable summaries of data with high spatial and temporal resolution. This approach differs from many common methods for comparing gaze behavior between natural groups, which usually only include single-dimensional features such as the duration of fixation on a particular part of the stimulus. The method is illustrated by contrasting a sample of a group of persons with particularly high cognitive abilities (high achievement on IQ tests) with a control group on a psycholinguistic task on the conceptualization of motion events. In the example, we find no substantive differences in relative importance, but more exploratory gaze behavior in the highly gifted group. The code, videos, and eye-tracking data we used for this study are available online.