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.

Chromatin architecture, a key regulator of gene expression, is inferred through chromatin contacts. However, classical analyses of chromosome conformation data do not preserve multi-way relationships. Here we use long sequencing reads to map genome-wide multi-way contacts and investigate higher order chromatin organization of the human genome. We use the theory of hypergraphs for data representation and analysis, and quantify higher order structures in primary human fibroblasts and B lymphocytes. Through integration of multi-way contact data with chromatin accessibility, gene expression, and transcription factor binding data, we introduce a data-driven method to extract transcriptional clusters.