Inhomogeneous patterns of chromatin-chromatin contacts within 10–100-kb-sized regions of the genome are a generic feature of chromatin spatial organization. These features, termed topologically associating domains (TADs), have led to the loop extrusion factor (LEF) model. Currently, our ability to model TADs relies on the observation that in vertebrates TAD boundaries are correlated with DNA sequences that bind CTCF, which therefore is inferred to block loop extrusion. However, although TADs feature prominently in their Hi-C maps, non-vertebrate eukaryotes either do not express CTCF or show few TAD boundaries that correlate with CTCF sites. In all of these organisms, the counterparts of CTCF remain unknown, frustrating comparisons between Hi-C data and simulations. To extend the LEF model across the tree of life, here, we propose the conserved-current loop extrusion (CCLE) model that interprets loop-extruding cohesin as a nearly conserved probability current. From cohesin ChIP-seq data alone, we derive a position-dependent loop extrusion rate, allowing for a modified paradigm for loop extrusion, that goes beyond solely localized barriers to also include loop extrusion rates that vary continuously. We show that CCLE accurately predicts the TAD-scale Hi-C maps of interphase Schizosaccharomyces pombe, as well as those of meiotic and mitotic Saccharomyces cerevisiae, demonstrating its utility in organisms lacking CTCF. The success of CCLE in yeasts suggests that loop extrusion by cohesin is indeed the primary mechanism underlying TADs in these systems. CCLE allows us to obtain loop extrusion parameters such as the LEF density and processivity, which compare well to independent estimates.

中文翻译：

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仅粘连蛋白分布即可通过守恒电流回路挤出预测酵母中的染色质组织


在基因组的 10-100 kb 大小的区域内，染色质-染色质接触的不均匀模式是染色质空间组织的一个通用特征。这些特征称为拓扑关联域 （TAD），导致了环拉伸因子 （LEF） 模型。目前，我们模拟 TAD 的能力依赖于这样一个观察结果，即在脊椎动物中，TAD 边界与结合 CTCF 的 DNA 序列相关，因此被推断为块状环挤出。然而，尽管 TADs 在其 Hi-C 图谱中占有突出地位，但非脊椎动物真核生物要么不表达 CTCF，要么显示很少与 CTCF 位点相关的 TAD 边界。在所有这些生物体中，CTCF 的对应物仍然未知，这使得 Hi-C 数据和模拟之间的比较令人沮丧。为了将 LEF 模型扩展到生命之树，我们在这里提出了守恒电流回路挤压 （CCLE） 模型，该模型将回路挤压内聚蛋白解释为几乎守恒的概率电流。仅从粘连蛋白 ChIP-seq 数据中，我们得出了一个位置依赖性的环挤出速率，允许修改后的环挤出范例，它超越了单独的局部障碍，还包括连续变化的环挤出速率。我们表明 CCLE 准确预测了间期 Schizosaccharomyces pombe 的 TAD 尺度 Hi-C 图，以及减数分裂和有丝分裂酿酒酵母的 TAD 尺度 Hi-C 图，证明了它在缺乏 CTCF 的生物体中的效用。CCLE 在酵母中的成功表明，黏连蛋白的环挤出确实是这些系统中 TAD 的主要机制。CCLE 使我们能够获得环挤出参数，例如 LEF 密度和合成能力，这些参数与独立估计值非常相似。