Study of cell differentiation by phylogenetic analysis using histone modification data

Abstract

BackgroundIn cell differentiation, a cell of a less specialized type becomes one of a more specialized type, even though all cells have the same genome. Transcription factors and epigenetic marks like histone modifications can play a significant role in the differentiation process.ResultsIn this paper, we present a simple analysis of cell types and differentiation paths using phylogenetic inference based on ChIP-Seq histone modification data. We precisely defined the notion of cell-type trees and provided a procedure of building such trees. We propose new data representation techniques and distance measures for ChIP-Seq data and use these together with standard phylogenetic inference methods to build biologically meaningful cell-type trees that indicate how diverse types of cells are related. We demonstrate our approach on various kinds of histone modifications for various cell types, also using the datasets to explore various issues surrounding replicate data, variability between cells of the same type, and robustness. We use the results to get some interesting biological findings like important patterns of histone modification changes during cell differentiation process.ConclusionsWe introduced and studied the novel problem of inferring cell type trees from histone modification data. The promising results we obtain point the way to a new approach to the study of cell differentiation. We also discuss how cell-type trees can be used to study the evolution of cell types.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2105-15-269) contains supplementary material, which is available to authorized users.

A maximum-likelihood approach for building cell-type trees by lifting

“…First, as mentioned before, we know that cell differentiation transforms less specialized cell types into more specialized ones. Since this transformation is unidirectional, the paths of differentiation can be represented as a tree structure, much as is done with the phylogenetic trees used to represent evolutionary histories [ 7 ]. The similarity between the two extends further: cell types themselves have evolved into larger collections from more restricted collections in early ancestors: there are phylogenetic relationships among the various types of cells.…”

“…As in Kin et al work [ 2 ], they found that the RNA-Seq data contain significant tree structures. In earlier work [ 7 ], we also calculated a statistical measure to show that the distances we computed are in fact representative of a tree. Thus multiple studies on different kinds of datasets—ChIP-Seq in our case, RNA-seq in the other two papers—support the tree-like relationship of cell types and underscore the usefulness of the cell-type tree (as noted in [ 2 ]).…”

“…Therefore, it becomes important to be able to infer which cell types should be treated as the ancestor, or parent, of another. Our earlier work [ 7 , 13 ] focused on the use of distance-based and parsimony-based phylogenetic methods to infer the tree, not the ancestors. Here we propose an ML approach to the inference of cell-type trees on histone modification data and proceed to derive a new algorithm to infer the internal nodes by a process known as lifting.…”

Inferring cell type innovations by phylogenetic methods—concepts, methods, and limitations

“…Using assumptions similar to the one described above, several authors have recently reconstructed the cell type tree from highthroughput sequencing data (Nair et al, 2014;Kin et al, 2015;Koyanagi, 2015;Liang et al, 2015). Nair et al and Koyanagi used epigenomic information for the reconstruction.…”

Confident gene activity prediction based on single histone modification H2BK5ac in human cell lines

“…An octamer that contains two of each of the four histones H2A, H2B, H3, and H4 constitutes the protein core of each nucleosome, and its nucleic acid component consists of 147 bp of dsDNA wrapped around the surface of the protein core. Consecutive nucleosomes are separated approximately by 60 bp of DNA [1–4]. The nucleosome histones are subject to covalent post-translational modifications, the most frequent of which are methylations and acetylations [5–7].…”