In:
PLOS Biology, Public Library of Science (PLoS), Vol. 20, No. 10 ( 2022-10-26), p. e3001849-
Abstract:
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 pass 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 coexpression 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 24 h 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 down-regulation 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 h. These observations suggest that the nonspecificity of genome decompaction is the condition for the generation of a highly variable multilineage expression profile. The nonspecific 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 recompaction. Thus, the initiation of differentiation is reminiscent of a constrained optimization 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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001849
DOI:
10.1371/journal.pbio.3001849.g001
DOI:
10.1371/journal.pbio.3001849.g002
DOI:
10.1371/journal.pbio.3001849.g003
DOI:
10.1371/journal.pbio.3001849.g004
DOI:
10.1371/journal.pbio.3001849.g005
DOI:
10.1371/journal.pbio.3001849.g006
DOI:
10.1371/journal.pbio.3001849.s001
DOI:
10.1371/journal.pbio.3001849.s002
DOI:
10.1371/journal.pbio.3001849.s003
DOI:
10.1371/journal.pbio.3001849.s004
DOI:
10.1371/journal.pbio.3001849.s005
DOI:
10.1371/journal.pbio.3001849.s006
DOI:
10.1371/journal.pbio.3001849.s007
DOI:
10.1371/journal.pbio.3001849.s008
DOI:
10.1371/journal.pbio.3001849.s009
DOI:
10.1371/journal.pbio.3001849.s010
DOI:
10.1371/journal.pbio.3001849.s011
DOI:
10.1371/journal.pbio.3001849.s012
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2126773-X
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