Development and application of combinatorial single cell methods to tissue physiology and disease

Abstract

Advances in single-cell sequencing technologies present an opportunity to study the cellular and molecular basis of complex tissue physiology at global scale with unprecedented throughput. In this work, methods for application of a method of single cell sequencing – single-cell combinatorial indexing (“sci”) methods – were extended for use in mammalian tissue. In the human heart, analysis of single nucleus data reveals variation by age and sex in healthy donors, divergent use of transcription factor motifs in adult vs. fetal chromatin, and distal genomic sites that improve predictive models of cell type-specific expression. In mouse models of lung disease, we find aberrant differentiation states in the macrophages of a model of pulmonary alveolar proteinosis, emergence of an osteoclast-like macrophage phenotype in a model of silicosis, and in both models we find widespread alterations across the cell types of the lung. In overlapping work, we build interpretable predictive models of gene expression in the human heart and in the P. falciparum parasite, finding cell-type specific transcription factors in adult human heart and uncovering strikingly stage-specific information content in histone marks in Plasmodium.