标题： 转录沉默的建模及其与三维基因组组织的耦合 显示英文标题

标题： Modelling transcriptional silencing and its coupling to 3D genome organisation

摘要： 及时的基因表达上调或下调对于细胞分化和功能至关重要。 虽然通过转录激活因子的基因上调已被广泛研究，但基因沉默仍研究不足，尤其是在建模方面。 本研究采用三维模拟来研究染色质纤维的生物物理特性，其中活跃的转录因子与抑制因子在纤维上的转录单元上竞争结合，并探讨不同的沉默机制如何影响三维染色质结构和转录。 我们检查了三种基因沉默反馈机制：正反馈、负反馈和中性反馈。 这些机制捕捉了在生物系统中观察到或提出的不同沉默途径。 我们的研究结果表明，尽管所有机制都会导致沉默转变，但这种转变的特征取决于反馈的选择。 后者控制着出现的三维转录因子聚集体的形态、平均基因表达及其变异性，或基因噪声，以及相邻转录单元活动之间的相关网络。 这些结果为基因沉默的生物物理特性以及转录调控与三维基因组组织之间的相互作用提供了见解。 显示英文摘要

摘要： Timely up- or down-regulation of gene expression is crucial for cellular differentiation and function. While gene upregulation via transcriptional activators has been extensively investigated, gene silencing remains understudied, especially by modelling. This study employs 3D simulations to study the biophysics of a chromatin fibre where active transcription factors compete with repressors for binding to transcription units along the fibre, and investigates how different silencing mechanisms affect 3D chromatin structure and transcription. We examine three gene silencing feedback mechanisms: positive, negative, and neutral. These mechanisms capture different silencing pathways observed or proposed in biological systems. Our findings reveal that, whilst all mechanisms lead to a silencing transition, the signatures of this transition depend on the choice of the feedback. The latter controls the morphologies of the emergent 3D transcription factor clusters, the average gene expression and its variability, or gene noise, and the network of ensuing correlations between activities of neighbouring transcription units. These results provide insights into the biophysics of gene silencing, as well as into the interplay between transcriptional regulation and 3D genome organisation.