Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Mathematics, University of California-Irvine, Irvine, CA 92697, USA.
Genes (Basel). 2023 Dec 9;14(12):2193. doi: 10.3390/genes14122193.
Transient DNA loops occur throughout the genome due to thermal fluctuations of DNA and the function of SMC complex proteins such as condensin and cohesin. Transient crosslinking within and between chromosomes and loop extrusion by SMCs have profound effects on high-order chromatin organization and exhibit specificity in cell type, cell cycle stage, and cellular environment. SMC complexes anchor one end to DNA with the other extending some distance and retracting to form a loop. How cells regulate loop sizes and how loops distribute along chromatin are emerging questions. To understand loop size regulation, we employed bead-spring polymer chain models of chromatin and the activity of an SMC complex on chromatin. Our study shows that (1) the stiffness of the chromatin polymer chain, (2) the tensile stiffness of chromatin crosslinking complexes such as condensin, and (3) the strength of the internal or external tethering of chromatin chains cooperatively dictate the loop size distribution and compaction volume of induced chromatin domains. When strong DNA tethers are invoked, loop size distributions are tuned by condensin stiffness. When DNA tethers are released, loop size distributions are tuned by chromatin stiffness. In this three-way interaction, the presence and strength of tethering unexpectedly dictates chromatin conformation within a topological domain.
由于 DNA 的热波动以及 SMC 复合物蛋白（如 condensin 和 cohesin）的功能，瞬时 DNA 环会出现在整个基因组中。SMC 介导的染色体内部和之间的瞬时交联以及环的挤出对高级染色质组织有深远的影响，并在细胞类型、细胞周期阶段和细胞环境中表现出特异性。SMC 复合物将其一端固定在 DNA 上，另一端延伸一定距离并回缩以形成环。细胞如何调节环的大小以及环如何沿染色质分布是当前的研究问题。为了理解环的大小调节，我们采用了染色质珠-弹簧聚合物链模型以及 SMC 复合物在染色质上的活性。我们的研究表明：（1）染色质聚合物链的刚性；（2）诸如 condensin 等染色质交联复合物的拉伸刚性；以及（3）染色质链的内部或外部束缚的强度，共同决定了诱导染色质域的环大小分布和压缩体积。当存在强 DNA 束缚时，环的大小分布由 condensin 刚性调节。当释放 DNA 束缚时，环的大小分布由染色质刚性调节。在这种三向相互作用中，束缚的存在和强度出人意料地决定了拓扑域内的染色质构象。
