Inter-chromosomal contacts demarcate genome topology along a spatial gradient

Area of Science:

• Genomics
• Molecular Biology
• Bioinformatics

Background:

• Non-homologous chromosomal contacts (NHCCs) play a significant role in gene and genome regulation.
• Analytical challenges have limited the understanding of NHCC extent and principles across cell types, leading to their perception as stochastic events.

Purpose of the Study:

• To develop and apply a novel algorithm, Signature, for identifying NHCCs in Hi-C datasets.
• To characterize the properties and genomic locations of NHCCs across diverse human cell types.
• To elucidate the role of NHCCs in genome topology and gene regulation.

Main Methods:

• Development of a supervised and unsupervised learning algorithm named Signature.
• Application of Signature to analyze 62 Hi-C datasets from 53 diploid human cell types.
• Genomic and functional characterization of identified NHCCs.

Main Results:

• Identification of 40,282 NHCCs and their properties across human cell types.
• Genomic regions involved in NHCCs are gene-dense, highly expressed, and associated with cell- and sex-specific functions.
• Discovery of extensive inter-telomeric and inter-centromeric clustering, with 61 constitutive NHCCs consistently located at nuclear speckles.

Conclusions:

• NHCCs are non-randomly positioned and significantly shape genome topology.
• Constitutive NHCCs act as 'anchor loci,' establishing an axis of genome activity.
• Cell-type-specific NHCCs form discrete hubs, contributing to a spatial gradient of genome activity.