In vivo dissection of a clustered-CTCF domain boundary reveals developmental principles of regulatory insulation

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Item Type:

Article

Title:

In vivo dissection of a clustered-CTCF domain boundary reveals developmental principles of regulatory insulation

Creators Name:

Anania, C. and Acemel, R.D. and Jedamzick, J. and Bolondi, A. and Cova, G. and Brieske, N. and Kühn, R. and Wittler, L. and Real, F.M. and Lupiáñez, D.G.

Abstract:

Vertebrate genomes organize into topologically associating domains, delimited by boundaries that insulate regulatory elements from nontarget genes. However, how boundary function is established is not well understood. Here, we combine genome-wide analyses and transgenic mouse assays to dissect the regulatory logic of clustered-CCCTC-binding factor (CTCF) boundaries in vivo, interrogating their function at multiple levels: chromatin interactions, transcription and phenotypes. Individual CTCF binding site (CBS) deletions revealed that the characteristics of specific sites can outweigh other factors such as CBS number and orientation. Combined deletions demonstrated that CBSs cooperate redundantly and provide boundary robustness. We show that divergent CBS signatures are not strictly required for effective insulation and that chromatin loops formed by nonconvergently oriented sites could be mediated by a loop interference mechanism. Further, we observe that insulation strength constitutes a quantitative modulator of gene expression and phenotypes. Our results highlight the modular nature of boundaries and their control over developmental processes.

Keywords:

Binding Sites, CCCTC-Binding Factor, Chromatin, Chromosomes, Genome, Genome-Wide Association Study, Animals, Mice

Source:

Nature Genetics

ISSN:

1061-4036

Publisher:

Nature Publishing Group

Date:

July 2022

Official Publication:

https://doi.org/10.1038/s41588-022-01117-9