Abstract
The DNA microstates that regulate transcription include sequence-specific transcription factors (TFs), coregulatory complexes, nucleosomes, histone modifications, DNA methylation, and parts of the three-dimensional architecture of genomes, which could create an enormous combinatorial complexity across the genome. However, many proteins and epigenetic marks are known to colocalize, suggesting that the information content encoded in these marks can be compressed. It has so far proved difficult to understand this compression in a systematic and quantitative manner. Here, we show that simple linear models can reliably predict the data generated by the ENCODE and Roadmap Epigenomics consortia. Further, we demonstrate that a small number of marks can predict all other marks with high average correlation across the genome, systematically revealing the substantial information compression that is present in different cell lines. We find that the linear models for activating marks are typically cell line-independent, while those for silencing marks are predominantly cell line-specific. Of particular note, a nuclear receptor corepressor, transducin beta-like 1 X-linked receptor 1 (TBLR1), was highly predictive of other marks in two hematopoietic cell lines. The methodology presented here shows how the potentially vast complexity of TFs, coregulators, and epigenetic marks at eukaryotic genes is highly redundant and that the information present can be compressed onto a much smaller subset of marks. These findings could be used to efficiently characterize cell lines and tissues based on a small number of diagnostic marks and suggest how the DNA microstates, which regulate the expression of individual genes, can be specified.
Highlights
The decision to transcribe genes relies on DNA sequence information, which is interpreted by transcription factors (TFs) or other sequence-specific DNA-binding proteins
These genetic and epigenetic mechanisms “mark” regulatory loci to yield DNA microstates, a term derived from thermodynamics [1], which essentially considers any particular binding configuration of TFs and histone modification and DNA methylation patterns etc. that may arise at any time point at the regulatory loci of a gene of interest
Eukaryotic gene regulation is characterized by DNA microstates composed of TFs, coregulatory complexes, nucleosomes, histone modifications, DNA methylation, and parts of the three-dimensional architecture of genomes
Summary
The decision to transcribe genes relies on DNA sequence information, which is interpreted by transcription factors (TFs) or other sequence-specific DNA-binding proteins. TFs interact with a variety of mechanisms that reorganize chromatin structure, remodel nucleosomes, recruit coregulators, methylate DNA, and post-transcriptionally modify histones and regulatory proteins to collectively regulate transcription. These genetic and epigenetic mechanisms “mark” regulatory loci to yield DNA microstates, a term derived from thermodynamics [1], which essentially considers any particular binding configuration of TFs and histone modification and DNA methylation patterns etc. We showed how the functional relationship between the concentrations of TFs and the level of expression of a gene, known as the gene regulation function, can be calculated by determining the relevant microstates and the rates of transition between them [1]
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