GSE203567
Global genome decompaction leads to stochastic activation of gene expression as a first step toward fate commitment in human hematopoietic cells [scATAC-seq]
When human cord blood derived CD34+ cells are induced to differentiate, they undergo rapid and dynamic morphological and molecular transformations that are critical for fate commitment. In particular, the cells passe through a transitory phase known as “multilineage primed” state. These cells are characterized by a mixed gene expression profile, different in each cell, with the co-expression of many genes characteristic for concurrent cell lineages. The aim of our study is to understand the mechanisms of the establishment and the exit from this transitory state. We investigated this issue using single-cell RNA sequencing and ATAC-seq. Two phases were detected. The first phase is a rapid and global chromatin decompaction that makes most of the gene promoters in the genome accessible for transcription. It results 24h later in enhanced and pervasive transcription of the genome leading to the concomitant increase in the cell-to-cell variability of transcriptional profiles. The second phase is the exit from the multilineage-primed phase marked by a slow chromatin closure and a subsequent overall downregulation of gene transcription. This process is selective and results in the emergence of coherent expression profiles corresponding to distinct cell subpopulations. The typical time scale of these events spans 48 to 72 hours. These observations suggest that the non-specificity of genome decompaction is the condition for the generation of a highly variable multilineage expression profile. The non-specific phase is followed by specific regulatory actions that stabilize and maintain the activity of key genes, while the rest of the genome becomes repressed again by the chromatin re-compaction. Thus, the initiation of differentiation is reminiscent of a trial-and-error process that associates the spontaneous generation of gene expression diversity to subsequent regulatory actions that maintain the activity of some genes while the rest of the genome sinks back to the repressive closed chromatin state. Overall design: Evolution of single cell mRNA profile and DNA accessibility profile of HSC after cytokine stimulation