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Cell type-specific prediction of 3D chromatin organization enables high-throughput in silico genetic screening

ABSTRACT: Experimental methods for measuring 3D chromatin organization, such as Hi-C, are costly and have technical limitations, restricting their broad application particularly in high-throughput genetic perturbations. We present C.Origami, a deep neural network model that performs de novoprediction of cell type–specific chromatin organization using as inputs the DNA sequence and two cell type–specific genomic features — chromatin accessibility and CTCF binding. C.Origami predicts chromatin organization within a 2 mega-base window and enables in silico experiments to examine the impact of genetic perturbations on chromatin interactions in pathologies such as cancer. We assess how individual DNA elements contribute to the organization of 3D chromatin organization and identify a compendium of cell type–specific trans-regulators across multiple cell types. We demonstrate that cell type–specific in silico genetic perturbation and screening, enabled by C.Origami, can be used to systematically discover chromatin regulatory mechanisms in both normal and disease-related biological systems.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216430 | GEO | 2022/10/31

REPOSITORIES: GEO

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Project description:The genome adopts varied and specific 3D conformations in different cell types. The loop extruding factor, cohesin, is thought to play a key role in the formation of this 3D structure, however it is unknown how cell-type specificity is achieved. One proposed mechanism is that cis-regulatory elements, which are active in unique combinations in different cell types, recruit cohesin and therefore direct the formation of specific 3D conformation. We have identified genome-wide natural variation in enhancer sites in healthy human donors, by performing cohesin ChIP-seq in these cells we show that cohesin occupancy is directly correlated with enhancer activity. Identification of the genetic variants associated with the gain or loss of enhancer-like elements and associating this with the recruitment of cohesin provides evidence of a direct link between widespread genetic variation in the non-coding genome and cell-specific changes in 3D genome organization. Therefore, enhancer elements have evolved not only the ability to upregulate transcription at promoters, but also the ability to stimulate the mechanisms that insure robust interactions between them. Next, using enhancer KO models in the well characterised alpha globin locus, we show how cohesin recruitment and 3D genome organization correlates with changes in the local regulatory landscape. We then selected the strongest of the alpha globin enhancers and inserted it into a neutral region of the genome, to test if a single active enhancer was capable of recruiting cohesin and initiating the formation of a 3D chromatin domain when isolated from its native context. Our results show that an enhancer is able to direct the recruitment of cohesin when in an active state and that this is correlated with changes in the local chromatin environment, giving rise to open chromatin sites and de novo chromatin interactions in an otherwise “neutral” region of the genome. These results support the hypothesis that tissue-specific recruitment of cohesin is facilitated by enhancers and that this plays a role in establishing cell-specific changes in 3D genome conformation.

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Cell type-specific prediction of 3D chromatin organization enables high-throughput in silico genetic screening

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