Abstract
Genome conformation capture techniques permit a systematic investigation into the functional spatial organization of genomes, including functional aspects like assessing the co-localization of sets of genomic elements. For example, the co-localization of genes targeted by a transcription factor (TF) within a transcription factory. We quantify spatial co-localization using a rigorous statistical model that measures the enrichment of a subset of elements in neighbourhoods inferred from Hi-C data. We also control for co-localization that can be attributed to genomic order. We systematically apply our open-sourced framework, spatial-mHG, to search for spatial co-localization phenomena in multiple unicellular Hi-C datasets with corresponding genomic annotations. Our biological findings shed new light on the functional spatial organization of genomes, including: In C. crescentus, DNA replication genes reside in two genomic clusters that are spatially co-localized. Furthermore, these clusters contain similar gene copies and lay in genomic vicinity to the ori and ter sequences. In S. cerevisae, Ty5 retrotransposon family element spatially co-localize at a spatially adjacent subset of telomeres. In N. crassa, both Proteasome lid subcomplex genes and protein refolding genes jointly spatially co-localize at a shared location. An implementation of our algorithms is available online.
Highlights
Studying the co-localization of elements along the genome[1] is used for providing evidence of evolutionary or mechanistic relationships between genomic elements and genomic organization
Studies pertaining to the underlying mechanism of topologically associated domains (TADs) formation have implicated the contribution of CTCF and cohesin, key contributors to cell-type-specific genome conformation[15]
We observe a previously known preference of family Ty5 to associate to peri-telomeric regions. While this association was already known, we offer a refinement in such that the 8 annotated Ty5 long terminal repeats (LTRs) elements tend to co-localize at a specific hemisphere of the nucleus, on chromosomes III (3 instances), V (2 instances), VII, VIII and XI
Summary
Studying the co-localization of elements along the genome[1] is used for providing evidence of evolutionary or mechanistic relationships between genomic elements and genomic organization. Chromosome conformation capture (3C) and methods derived therefrom (Hi-C)[2,3] are, generally speaking, experimental protocols that yield a sparse map of paired sequencing read counts These counts correlate with 3D spatial proximities between pairs of genomic loci[4]. Hi-C has established a prominent and noteworthy contribution to our understanding of cis chromatin order and epigenetics with progress in the study and characterization of topologically associated domains (TADs)[12,13,14] Such domains are typically presented as local triangle-shapes in a triangular view of the Hi-C interaction matrix, corresponding to local clusters of high intra-cluster, low inter-cluster read density. A later study[18], followed with a systematic analysis using independent 3C (chromosome conformation capture) and 3D-FISH experiments Their results provided early evidence to the dynamic nature of co-localization of active genes. We developed streamlined algorithmic and statistical approaches as described
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