Exploring the Physical Genome

Abstract:

Chromatin accessibility is a powerful lens to explore mechanisms of gene expression regulation, as regions of increased chromatin accessibility represent genetic elements that have the potential to regulate gene expression. To define the open chromatin landscape in primary human tissue, we collected single-cell chromatin accessibility profiles across 10 populations of immunophenotypically defined human hematopoietic cell types and constructed a chromatin accessibility landscape of human hematopoiesis to characterize differentiation trajectories. We find variation consistent with lineage bias toward different developmental branches in multipotent cell types. We observe heterogeneity within common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) and develop a strategy to partition GMPs along their differentiation trajectory.

Furthermore, we integrated single-cell RNA sequencing (scRNA-seq) data to associate transcription factors to chromatin accessibility changes and regulatory elements to target genes through correlations of expression and regulatory element accessibility. Overall, this work provides a framework for integrative exploration of complex regulatory dynamics in a primary human tissue at single-cell resolution. We have also recently completed a survey of the chromatin accessibility landscape in primary human tumor tissue, providing a catalog of regulatory elements across human cancers.