Department of Biochemistry, University of California, Riverside, 3401 Watkins Drive, Boyce Hall, Riverside, CA, 92521, United States.
Stem Cell Center, University of California, Riverside, 900 University Ave, Riverside, CA, 92521, United States.
Nat Commun. 2022 Apr 29;13(1):2350. doi: 10.1038/s41467-022-29730-6.
Cell fate commitment is driven by dynamic changes in chromatin architecture and activity of lineage-specific transcription factors (TFs). The chromatin assembly factor-1 (CAF-1) is a histone chaperone that regulates chromatin architecture by facilitating nucleosome assembly during DNA replication. Accumulating evidence supports a substantial role of CAF-1 in cell fate maintenance, but the mechanisms by which CAF-1 restricts lineage choice remain poorly understood. Here, we investigate how CAF-1 influences chromatin dynamics and TF activity during lineage differentiation. We show that CAF-1 suppression triggers rapid differentiation of myeloid stem and progenitor cells into a mixed lineage state. We find that CAF-1 sustains lineage fidelity by controlling chromatin accessibility at specific loci, and limiting the binding of ELF1 TF at newly-accessible diverging regulatory elements. Together, our findings decipher key traits of chromatin accessibility that sustain lineage integrity and point to a powerful strategy for dissecting transcriptional circuits central to cell fate commitment.
细胞命运的决定是由染色质结构和谱系特异性转录因子（TFs）的活性的动态变化驱动的。染色质组装因子-1（CAF-1）是一种组蛋白伴侣，通过在 DNA 复制过程中促进核小体组装来调节染色质结构。越来越多的证据支持 CAF-1 在维持细胞命运方面的重要作用，但 CAF-1 限制谱系选择的机制仍知之甚少。在这里，我们研究了 CAF-1 如何在谱系分化过程中影响染色质动力学和 TF 活性。我们表明，CAF-1 的抑制会促使髓系干细胞和祖细胞迅速分化为混合谱系状态。我们发现，CAF-1 通过控制特定基因座的染色质可及性，并限制 ELF1 TF 在新可及的发散调控元件上的结合，从而维持谱系保真度。总之，我们的研究结果揭示了维持谱系完整性的染色质可及性的关键特征，并为剖析对细胞命运决定至关重要的转录回路提供了一种强大的策略。
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