Abstract
Chromatin accessibility, as measured by ATACseq, varies between hematopoietic cell types in different lineages of the hematopoietic differentiation tree, e.g. T cells vs. B cells, but methods that associate variation in chromatin accessibility to the lineage structure of the differentiation tree are lacking. Using an ATACseq dataset recently published by the ImmGen consortium, we construct associations between chromatin accessibility and hematopoietic cell types using a novel co-clustering approach that accounts for the structure of the hematopoietic, differentiation tree. Under a model in which all loci and cell types within a co-cluster have a shared accessibility state, we show that roughly 80% of cell type associated accessibility variation can be captured through 12 cell type clusters and 20 genomic locus clusters, with the cell type clusters reflecting coherent components of the differentiation tree. Using publicly available ChIPseq datasets, we show that our clustering reflects transcription factor binding patterns with implications for regulation across cell types. We show that traditional methods such as hierarchical and kmeans clusterings lead to cell type clusters that are more dispersed on the tree than our tree-based algorithm. We provide a python package, chromcocluster, that implements the algorithms presented.
Highlights
The development of the ATACseq technique over the past decade has spurred a broad investigation of chromatin accessibility across cell types (Buenrostro et al, 2013; Klemm et al, 2019)
Are most accessible genomic loci accessible only in a specific, cell type or are a significant number of loci accessible jointly across a particular collections of cell types? If many loci are accessible across a particular collection of cell types, do those cell types form connected components of the differentiation tree, or are they dispersed? More generally, how do we quantitatively find and describe associations between chromatin accessibility and the differentiation tree? And if such associations exist, how do they shape cellular regulation? Answering these questions would provide a context in which to analyze the chromatin accessibility of particular hematopoietic cell types and to understand differences in cellular regulation across the hematopoietic cell types
The Yoshida et al dataset includes ATACseq libraries across 90 cell types, but we restricted our attention to the 78 cell types derived from adult, bone marrow derived, hematopoietic stem cells, i.e. HSCs (Seita and Weissman, 2010)
Summary
The development of the ATACseq technique over the past decade has spurred a broad investigation of chromatin accessibility across cell types (Buenrostro et al, 2013; Klemm et al, 2019). Chromatin accessibility has been intensively studied using ATACseq across many hematopoietic cells types (Lara-Astiaso et al, 2014; Corces et al, 2016; Scott-Browne et al, 2016; Lau et al, 2018; Calderon et al, 2019; Yoshida et al, 2019; Sun and Barreiro, 2020; Xiang et al, 2020). Co-Clustering Hematopoietic Chromatin Accessibility reflects the form of the differentiation tree. In this context, many questions remain unanswered. Answering these questions would provide a context in which to analyze the chromatin accessibility of particular hematopoietic cell types and to understand differences in cellular regulation across the hematopoietic cell types Are most accessible genomic loci accessible only in a specific, cell type or are a significant number of loci accessible jointly across a particular collections of cell types (e.g. all T cells)? If many loci are accessible across a particular collection of cell types, do those cell types form connected components of the differentiation tree, or are they dispersed? More generally, how do we quantitatively find and describe associations between chromatin accessibility and the differentiation tree? And if such associations exist, how do they shape cellular regulation? Answering these questions would provide a context in which to analyze the chromatin accessibility of particular hematopoietic cell types and to understand differences in cellular regulation across the hematopoietic cell types
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