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Data on genome organization and output over time, or the 4D Nucleome (4DN), require synthesis for meaningful interpretation. Development of tools for the efficient integration of these data is needed, especially for the time dimension. We present the ‘4DNvestigator’, a user-friendly network-based toolbox for the analysis of time series genome-wide genome structure (Hi-C) and gene expression (RNA-seq) data. Additionally, we provide methods to quantify network entropy, tensor entropy, and statistically significant changes in time series Hi-C data at different genomic scales.

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In biological and engineering systems, structure, function and dynamics are highly coupled. Such interactions can be naturally and compactly captured via tensor based state space dynamic representations. However, such representations are not amenable to the standard system and controls framework which requires the state to be in the form of a vector. In order to address this limitation, recently a new class of multiway dynamical systems has been introduced in which the states, inputs and outputs are tensors. We propose a new form of multilinear time invariant (MLTI) systems based on the Einstein product and even-order paired tensors. We extend classical linear time invariant (LTI) system notions including stability, reachability and observability for the new MLTI system representation by leveraging recent advances in tensor algebra.

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Chromatin architecture, a key regulator of gene expression, can be inferred using chromatin contact data from chromosome conformation capture, or Hi-C. However, classical Hi-C does not preserve multi-way contacts. Here we use long sequencing reads to map genome-wide multi-way contacts and investigate higher order chromatin organization in the human genome. We use hypergraph theory for data representation and analysis, and quantify higher order structures in neonatal fibroblasts, biopsied adult fibroblasts, and B lymphocytes. By integrating multi-way contacts with chromatin accessibility, gene expression, and transcription factor binding, we introduce a data-driven method to identify cell type-specific transcription clusters. We provide transcription factor-mediated functional building blocks for cell identity that serve as a global signature for cell types.