Global genome decompaction leads to stochastic activation of gene expression as a first step toward fate commitment in human hematopoietic cells [ATAC-seq]

When human cord blood derived CD34+ cells are induced to differentiate in vitro, they undergo rapid and dynamic morphological and molecular transformation that are critical for the fate commitment. Using ATAC-seq and single-cell RNA sequencing we detected two phases of this process. We show that a rapid and widespread chromatin opening - that makes most of the gene promoters in the genome accessible - precedes the high and unrestrained transcription of a large variety of genes. This phase results in a quasi-random gene expression profile unique to each cell. During the second phase, slow chromatin closing precedes the downregulation of transcription and the emergence of coherent expression profiles. Transcription factors may play a role in the maintenance of the transcription activity of their target genes rather than in their initial activation. These observations are consistent with a model based on the spontaneous probabilistic organization of the cellular process of fate commitment. Overall design: Evolution of single cell mRNA profile and DNA accessibility profile of HSC after cytokine stimulation

人脐带血来源的CD34+细胞（CD34+ cells）在体外诱导分化过程中，会经历快速且动态的形态与分子层面转变，该过程对细胞命运决定至关重要。本研究通过转座酶可及性测序（ATAC-seq）与单细胞RNA测序（single-cell RNA sequencing），解析了该分化过程的两个阶段。研究发现，各类基因出现高水平且无限制的转录之前，会先发生快速且广泛的染色质开放——这一过程可使基因组中绝大多数基因启动子获得染色质可及性。该阶段会形成每个细胞独有的准随机基因表达谱。在第二阶段，缓慢的染色质闭合先于转录下调与协调一致基因表达谱的形成发生。转录因子可能主要参与维持靶基因的转录活性，而非介导其初始激活过程。上述观测结果与基于细胞命运决定过程的自发概率性组织所构建的模型一致。实验整体设计：细胞因子刺激后，造血干细胞（HSC）的单细胞mRNA表达谱与DNA可及性谱的动态演化过程。