Abstract
Gene expression is controlled by the concerted interactions between transcription factors and chromatin regulators. While recent studies have identified global chromatin state changes across cell-types, it remains unclear to what extent these changes are co-regulated during cell-differentiation. Here we present a comprehensive computational analysis by assembling a large dataset containing genome-wide occupancy information of 5 histone modifications in 27 human cell lines (including 24 normal and 3 cancer cell lines) obtained from the public domain, followed by independent analysis at three different representations. We classified the differentiation stage of a cell-type based on its genome-wide pattern of chromatin states, and found that our method was able to identify normal cell lines with nearly 100% accuracy. We then applied our model to classify the cancer cell lines and found that each can be unequivocally classified as differentiated cells. The differences can be in part explained by the differential activities of three regulatory modules associated with embryonic stem cells. We also found that the “hotspot” genes, whose chromatin states change dynamically in accordance to the differentiation stage, are not randomly distributed across the genome but tend to be embedded in multi-gene chromatin domains, and that specialized gene clusters tend to be embedded in stably occupied domains.
Highlights
Multi-cellular organisms are composed of diverse cell types that, despite sharing the same genome, are programmed with distinct gene expression patterns
We focused on 27 human cell lines for which data for all five modifications are available, including 24 normal and 3 cancer cell lines (Table S1)
To systematically compare different length scales, we analyzed the data independently based on three different representations, corresponding to increasing complex signatures: (1) the bin level sequence reads; (2) the gene-level summary scores associated with each histone mark; and (3) the combinatorial patterns of multiple histone marks referred to as the chromatin states
Summary
Multi-cellular organisms are composed of diverse cell types that, despite sharing the same genome, are programmed with distinct gene expression patterns. How such diversity is regulated mechanistically is a fundamental biological question. The fundamental unit of chromatin is nucleosome, a histone octamer, which wraps around 147 bp DNA. The N-terminal tails of histone proteins are decorated by different marks resulting from covalent modifications. The combinatorial patterns of these marks, which we refer to as the chromatin states, may recruit specific regulatory proteins, which in turn control transcription [1,2]
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