The interplay between the topological organization of the genome and the regulation of gene expression remains unclear. Depletion of molecular factors (e.g. CTCF) underlying topologically associating domains (TADs) leads to modest alterations in gene expression, while genomic rearrangements involving TAD boundaries disrupt normal gene expression and can lead to pathological phenotypes. Here we targeted the TAD neighbouring that of the noncoding transcript Xist, which controls X-chromosome inactivation. Inverting 245kb within the TAD led to expected rearrangement of CTCF-based contacts but revealed heterogeneity in the “contact” potential of different CTCF sites. Expression of most genes therein remained unaffected in mouse embryonic stem cells and during differentiation. Interestingly, expression of Xist was ectopically upregulated. The same inversion in mouse embryos led to biased Xist expression. Smaller inversions and deletions of CTCF clusters led to similar results: rearrangement of contacts, limited changes in local gene expression but significant changes in Xist expression in embryos. Our study suggests that the wiring of regulatory interactions within a TAD can influence the expression of genes in neighbouring TADs, highlighting the existence of mechanisms of inter-TAD communication.
Inversion of a topological domain leads to restricted changes in its gene expression and affects inter-domain communication
These authors contributed equally to the work
Present address: European Molecular Biology Laboratory, Heidelberg, Germany
Present address: Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
Present address: IGMM, Univ Montpellier, CNRS, Montpellier, France
- Award Group:
- Funder(s): Region Ile-de-France
- Award Id(s): DIM Biothrapies Fellowship
- Funder(s):
- Award Group:
- Funder(s): Fondation pour la Recherche Medicale
- Award Id(s): FDT20160435295 Fellowship
- Funder(s):
- Award Group:
- Funder(s): European Research Council
- Award Id(s): ERC-2014-AdG no. 671027 Advanced Investigator award
- Funder(s):
- Award Group:
- Funder(s): Labelisation La Ligue, FRM
- Award Id(s): DEI20151234398
- Funder(s):
- Award Group:
- Funder(s): ANR DoseX 2017, Labex DEEP
- Award Id(s): ANR-11-LBX-0044
- Funder(s):
- Award Group:
- Funder(s): IDEX PSL
- Award Id(s): ANR-10-IDEX-0001-02 PSL
- Funder(s):
- Award Group:
- Funder(s): ABS4NGS
- Award Id(s): ANR-11-BINF-0001
- Funder(s):
Currently Viewing Accepted Manuscript - Newer Version Available
Rafael Galupa, Christel Picard, Nicolas Servant, Elphège Pierre Nora, Yinxiu Zhan, Joke Gerarda van Bemmel, Fatima El Marjou, Colin Johanneau, Maud Borensztein, Katia Ancelin, Luca Giorgetti, Edith Heard; Inversion of a topological domain leads to restricted changes in its gene expression and affects inter-domain communication. Development 2022; dev.200568. doi: https://doi.org/10.1242/dev.200568
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