Genetics and Genome Biology Program, SickKids Research Institute, Toronto, ON, M5G 0A4, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Nat Commun. 2024 Nov 13;15(1):9813. doi: 10.1038/s41467-024-53983-y.
Non-homologous chromosomal contacts (NHCCs) between different chromosomes participate considerably in gene and genome regulation. Due to analytical challenges, NHCCs are currently considered as singular, stochastic events, and their extent and fundamental principles across cell types remain controversial. We develop a supervised and unsupervised learning algorithm, termed Signature, to call NHCCs in Hi-C datasets to advance our understanding of genome topology. Signature reveals 40,282 NHCCs and their properties across 62 Hi-C datasets of 53 diploid human cell types. Genomic regions of NHCCs are gene-dense, highly expressed, and harbor genes for cell-specific and sex-specific functions. Extensive inter-telomeric and inter-centromeric clustering occurs across cell types [Rabl's configuration] and 61 NHCCs are consistently found at the nuclear speckles. These constitutive 'anchor loci' facilitate an axis of genome activity whilst cell-type-specific NHCCs act in discrete hubs. Our results suggest that non-random chromosome positioning is supported by constitutive NHCCs that shape genome topology along an off-centered spatial gradient of genome activity.
非同源染色体接触（NHCCs）在不同染色体之间参与了相当多的基因和基因组调控。由于分析上的挑战，NHCCs 目前被认为是单一的、随机的事件，它们在细胞类型中的程度和基本原则仍然存在争议。我们开发了一种监督和无监督学习算法，称为 Signature，用于在 Hi-C 数据集中调用 NHCCs，以推进我们对基因组拓扑的理解。Signature 在 53 个人类二倍体细胞类型的 62 个 Hi-C 数据集中共揭示了 40282 个 NHCCs 及其特性。NHCCs 的基因组区域基因密度高、表达水平高，并且包含细胞特异性和性别特异性功能的基因。在细胞类型之间广泛发生端粒间和着丝粒间聚类[Rabl 构象]，并且在核斑点处始终发现 61 个 NHCCs。这些组成性的“锚定基因座”在基因组活性的轴线上提供了支持，而细胞类型特异性的 NHCCs 在离散的枢纽中起作用。我们的结果表明，非随机染色体定位得到组成性 NHCCs 的支持，这些 NHCCs 沿着基因组活性的偏心空间梯度塑造基因组拓扑。
