Abstract
In metazoans, each cell type follows a characteristic, spatio-temporally regulated DNA replication program. Histone modifications (HMs) and chromatin binding proteins (CBPs) are fundamental for a faithful progression and completion of this process. However, no individual HM is strictly indispensable for origin function, suggesting that HMs may act combinatorially in analogy to the histone code hypothesis for transcriptional regulation. In contrast to gene expression however, the relationship between combinations of chromatin features and DNA replication timing has not yet been demonstrated. Here, by exploiting a comprehensive data collection consisting of 95 CBPs and HMs we investigated their combinatorial potential for the prediction of DNA replication timing in Drosophila using quantitative statistical models. We found that while combinations of CBPs exhibit moderate predictive power for replication timing, pairwise interactions between HMs lead to accurate predictions genome-wide that can be locally further improved by CBPs. Independent feature importance and model analyses led us to derive a simplified, biologically interpretable model of the relationship between chromatin landscape and replication timing reaching 80% of the full model accuracy using six model terms. Finally, we show that pairwise combinations of HMs are able to predict differential DNA replication timing across different cell types. All in all, our work provides support to the existence of combinatorial HM patterns for DNA replication and reveal cell-type independent key elements thereof, whose experimental investigation might contribute to elucidate the regulatory mode of this fundamental cellular process.
Highlights
In eukaryotes, DNA replication is regulated both in time and space and initiates at multiple origins along the genome [1]
We found that predictions based on combinations of chromatin binding proteins (CBPs) and Histone modifications (HMs) exhibit a significantly lower cross-validated mean squared error (MSE) than the models trained on CBPs or HMs alone (Figure 1B) and thereby outperformed (r = 0.67, Supplementary Figure S4A) the accuracy of models solely based on CBPs (r~0:50, Supplementary Figure S3B) or HMs (r~0:61, Supplementary Figure S3D)
Our results show that combinations of HMs and their pairwise interactions are key in achieving accurate predictions, suggesting that combinatorial HM patters might contribute to the regulation of DNA
Summary
DNA replication is regulated both in time and space and initiates at multiple origins along the genome [1]. When averaged over a cell population, each genomic region shows reproducible replication timing in S-phase [2,3]. The timing of replication is a mitotically stable cell-type specific feature of chromosomes [4] that was recently legitimated as an epigenetic feature [5]. On one hand, established chromatin patterns of genome regulation are challenged by their disruption at the time of replication [8]. Very recent work shed light on basic principles that regulate DNA replication timing at a global level [10,11,12,13]
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