TAD border deletion at the Kit locus causes tissue-specific ectopic activation of a neighboring gene

Evelyn Kabirova, Anastasiya Ryzhkova, Varvara Lukyanchikova, Anna Khabarova, Alexey Korablev, Tatyana Shnaider, Miroslav Nuriddinov, Polina Belokopytova, Alexander Smirnov, Nikita V. Khotskin, Galina Kontsevaya, Irina Serova and Nariman Battulin ()
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Evelyn Kabirova: Institute of Cytology and Genetics SB RAS
Anastasiya Ryzhkova: Institute of Cytology and Genetics SB RAS
Varvara Lukyanchikova: Institute of Cytology and Genetics SB RAS
Anna Khabarova: Institute of Cytology and Genetics SB RAS
Alexey Korablev: Institute of Cytology and Genetics SB RAS
Tatyana Shnaider: Institute of Cytology and Genetics SB RAS
Miroslav Nuriddinov: Institute of Cytology and Genetics SB RAS
Polina Belokopytova: Institute of Cytology and Genetics SB RAS
Alexander Smirnov: Institute of Cytology and Genetics SB RAS
Nikita V. Khotskin: Institute of Cytology and Genetics SB RAS
Galina Kontsevaya: Institute of Cytology and Genetics SB RAS
Irina Serova: Institute of Cytology and Genetics SB RAS
Nariman Battulin: Institute of Cytology and Genetics SB RAS

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Topologically associated domains (TADs) restrict promoter-enhancer interactions, thereby maintaining the spatiotemporal pattern of gene activity. However, rearrangements of the TADs boundaries do not always lead to significant changes in the activity pattern. Here, we investigated the consequences of the TAD boundaries deletion on the expression of developmentally important genes encoding tyrosine kinase receptors: Kit, Kdr, Pdgfra. We used genome editing in mice to delete the TADs boundaries at the Kit locus and characterized chromatin folding and gene expression in pure cultures of fibroblasts, mast cells, and melanocytes. We found that although Kit is highly active in both mast cells and melanocytes, deletion of the TAD boundary between the Kit and Kdr genes results in ectopic activation only in melanocytes. Thus, the epigenetic landscape, namely the mutual arrangement of enhancers and actively transcribing genes, is important for predicting the consequences of the TAD boundaries removal. We also found that mice without a TAD border between the Kit and Kdr genes have a phenotypic manifestation of the mutation — a lighter coloration. Thus, the data obtained shed light on the principles of interaction between the 3D chromatin organization and epigenetic marks in the regulation of gene activity.

Date: 2024
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DOI: 10.1038/s41467-024-48523-7

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