ABSTRACT
Within the bone marrow, stem cells differentiate and give rise to diverse blood cell types and functions. Currently, hematopoietic progenitors are defined using surface markers combined with functional assays that are not directly linked with in vivo differentiation potential or gene regulatory mechanisms. Here, we comprehensively map myeloid progenitor subpopulations by transcriptional sorting of single cells from the bone marrow. We describe multiple progenitor subgroups, showing unexpected transcriptional priming toward seven differentiation fates but no progenitors with a mixed state. Transcriptional differentiation is correlated with combinations of known and previously undefined transcription factors, suggesting that the process is tightly regulated. Histone maps and knockout assays are consistent with early transcriptional priming, while traditional transplantation experiments suggest that in vivo priming may still allow for plasticity given strong perturbations. These data establish a reference model and general framework for studying hematopoiesis at single-cell resolution.
Subject(s)
Hematopoiesis , Myeloid Progenitor Cells/cytology , Myeloid Progenitor Cells/metabolism , Single-Cell Analysis , Transcriptome , Animals , Bone Marrow Transplantation , CCAAT-Enhancer-Binding Proteins/genetics , Gene Knockout Techniques , High-Throughput Nucleotide Sequencing , Mice , Mice, Inbred C57BL , Sequence Analysis, RNA , Transcription Factors/metabolismABSTRACT
MOTIVATION: Gene-gene interactions are of potential biological and medical interest, as they can shed light on both the inheritance mechanism of a trait and on the underlying biological mechanisms. Evidence of epistatic interactions has been reported in both humans and other organisms. Unlike single-locus genome-wide association studies (GWAS), which proved efficient in detecting numerous genetic loci related with various traits, interaction-based GWAS have so far produced very few reproducible discoveries. Such studies introduce a great computational and statistical burden by necessitating a large number of hypotheses to be tested including all pairs of single nucleotide polymorphisms (SNPs). Thus, many software tools have been developed for interaction-based case-control studies, some leading to reliable discoveries. For quantitative data, on the other hand, only a handful of tools exist, and the computational burden is still substantial. RESULTS: We present an efficient algorithm for detecting epistasis in quantitative GWAS, achieving a substantial runtime speedup by avoiding the need to exhaustively test all SNP pairs using metric embedding and random projections. Unlike previous metric embedding methods for case-control studies, we introduce a new embedding, where each SNP is mapped to two Euclidean spaces. We implemented our method in a tool named EPIQ (EPIstasis detection for Quantitative GWAS), and we show by simulations that EPIQ requires hours of processing time where other methods require days and sometimes weeks. Applying our method to a dataset from the Ludwigshafen risk and cardiovascular health study, we discovered a pair of SNPs with a near-significant interaction (P = 2.2 × 10(-13)), in only 1.5 h on 10 processors. AVAILABILITY: https://github.com/yaarasegre/EPIQ