Global genome decompaction leads to stochastic activation of gene expression as a first step toward fate commitment in human hematopoietic cells.
PLoS Biol, 20(10):e3001849.
When human cord blood-derived CD34+ cells are induced to differentiate, theyundergo rapid and dynamic morphological and molecular transformations that arecritical for fate commitment. In particular, the cells pass through a transitoryphase known as "multilineage-primed" state. These cells are characterized by amixed gene expression profile, different in each cell, with the coexpression ofmany genes characteristic for concurrent cell lineages. The aim of our study isto understand the mechanisms of the establishment and the exit from thistransitory state. We investigated this issue using single-cell RNA sequencing andATAC-seq. Two phases were detected. The first phase is a rapid and globalchromatin decompaction that makes most of the gene promoters in the genomeaccessible for transcription. It results 24 h later in enhanced and pervasivetranscription of the genome leading to the concomitant increase in thecell-to-cell variability of transcriptional profiles. The second phase is theexit from the multilineage-primed phase marked by a slow chromatin closure and asubsequent overall down-regulation of gene transcription. This process isselective and results in the emergence of coherent expression profilescorresponding to distinct cell subpopulations. The typical time scale of theseevents spans 48 to 72 h. These observations suggest that the nonspecificity ofgenome decompaction is the condition for the generation of a highly variablemultilineage expression profile. The nonspecific phase is followed by specificregulatory actions that stabilize and maintain the activity of key genes, whilethe rest of the genome becomes repressed again by the chromatin recompaction.Thus, the initiation of differentiation is reminiscent of a constrainedoptimization process that associates the spontaneous generation of geneexpression diversity to subsequent regulatory actions that maintain the activityof some genes, while the rest of the genome sinks back to the repressive closedchromatin state.
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