当细胞退出多能状态并开始致力于特定谱系时,它们必须激活适合该谱系的基因,同时沉默与多能性相关的基因并防止谱系不合适基因的激活。核小体重塑和去乙酰化(NuRD)复合物对于多能细胞成功进行谱系定型至关重要。NuRD控制调节序列的核小体密度,以促进转录反应。并且还已被证明可以防止未分化的多能细胞中的非计划转录(转录噪声)。尚未确定这些活动如何结合以确保细胞参与适合于成功谱系承诺的基因表达程序。在这里,我们表明NuRD不需要沉默所有的基因。相反,它限制了从多能状态退出后激活的基因的表达,但在自我更新条件下将它们保持在转录许可状态,这有助于它们在从幼稚多能性退出后的后续激活。我们进一步表明,NuRD协调基因表达变化,它的作用是在不同的稳定状态之间保持屏障。因此,NuRD介导的染色质重塑具有多种功能,包括减少转录噪音,激活和协调转录反应以促进谱系承诺的启动基因。
As cells exit the pluripotent state and begin to commit to a specific lineage they must activate genes appropriate for that lineage while silencing genes associated with pluripotency and preventing activation of lineage-inappropriate genes. The Nucleosome Remodelling and Deacetylation (
NuRD) complex is essential for pluripotent cells to successfully undergo lineage commitment.
NuRD controls nucleosome density at regulatory sequences to facilitate transcriptional responses, and also has been shown to prevent unscheduled transcription (transcriptional noise) in undifferentiated pluripotent cells. How these activities combine to ensure cells engage a gene expression program suitable for successful lineage commitment has not been determined. Here, we show that
NuRD is not required to silence all genes. Rather, it restricts expression of genes primed for activation upon exit from the pluripotent state, but maintains them in a transcriptionally permissive state in self-renewing conditions, which facilitates their subsequent activation upon exit from naïve pluripotency. We further show that
NuRD coordinates gene expression changes, which acts to maintain a barrier between different stable states. Thus
NuRD-mediated chromatin remodelling serves multiple functions, including reducing transcriptional noise, priming genes for activation and coordinating the transcriptional response to facilitate lineage commitment.