Both tissue-specific and ubiquitously expressed transcription factors, such as Sp-family members, are required for correct development. However, the molecular details of how ubiquitous factors are involved in programming tissue-specific chromatin and thus participate in developmental processes are still unclear. We previously showed that embryonic stem cells lacking Sp1 DNA-binding activity (Sp1ΔDBD/ΔDBD cells) are able to differentiate into early blood progenitors despite the inability of Sp1 to bind chromatin without its DNA-binding domain. However, gene expression during differentiation becomes progressively deregulated, and terminal differentiation is severely compromised. Here, we studied the cooperation of Sp1 with its closest paralogue Sp3 in hematopoietic development and demonstrate that Sp1 and Sp3 binding sites largely overlap. The complete absence of either Sp1 or Sp3 or the presence of the Sp1 DNA-binding mutant has only a minor effect on the pattern of distal accessible chromatin sites and their transcription factor binding motif content, suggesting that these mutations do not affect tissue-specific chromatin programming. Sp3 cooperates with Sp1ΔDBD/ΔDBD to enable hematopoiesis, but is unable to do so in the complete absence of Sp1. Using single-cell gene expression analysis, we show that the lack of Sp1 DNA binding leads to a distortion of cell fate decision timing, indicating that stable chromatin binding of Sp1 is required to maintain robust differentiation trajectories. Our findings highlight the essential contribution of ubiquitous factors such as Sp1 to blood cell development. In contrast to tissue-specific transcription factors which are required to direct specific cell fates, loss of Sp1 leads to a widespread deregulation in timing and coordination of differentiation trajectories during hematopoietic specification.

中文翻译：

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强大的造血规范需要无处不在的 Sp1 和 Sp3 转录因子。

组织特异性和普遍表达的转录因子，如 Sp 家族成员，都是正确发育所必需的。然而，普遍存在的因子如何参与编程组织特异性染色质并因此参与发育过程的分子细节仍不清楚。我们之前表明，缺乏 Sp1 DNA 结合活性的胚胎干细胞（Sp1ΔDBD/ΔDBD 细胞）能够分化为早期血液祖细胞，尽管 Sp1 在没有其 DNA 结合结构域的情况下无法结合染色质。然而，分化过程中的基因表达逐渐失调，终末分化受到严重损害。在这里，我们研究了 Sp1 与其最接近的旁系同源物 Sp3 在造血发育中的合作，并证明 Sp1 和 Sp3 结合位点在很大程度上重叠。Sp1 或 Sp3 的完全缺失或 Sp1 DNA 结合突变体的存在对远端可接近染色质位点的模式及其转录因子结合基序含量的影响很小，这表明这些突变不会影响组织特异性染色质编程。Sp3 与 Sp1ΔDBD/ΔDBD 合作以启用造血功能，但在完全没有 Sp1 的情况下无法这样做。使用单细胞基因表达分析，我们表明 Sp1 DNA 结合的缺乏导致细胞命运决定时间的扭曲，表明 Sp1 的稳定染色质结合是维持稳健分化轨迹所必需的。我们的研究结果强调了 Sp1 等普遍存在的因子对血细胞发育的重要贡献。