Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome

Srivarsha Rajshekar, Jun Yao, Paige K. Arnold, Sara G. Payne, Yinwen Zhang, Teresa V. Bowman, Robert J. Schmitz, John R. Edwards, Mary Goll

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Abstract

Pericentromeric satellite repeats are enriched in 5-methylcytosine (5mC). Loss of 5mC at these sequences is common in cancer and is a hallmark of Immunodeficiency, Centromere and Facial abnormalities (ICF) syndrome. While the general importance of 5mC is well-established, the specific functions of 5mC at pericentromeres are less clear. To address this deficiency, we generated a viable animal model of pericentromeric hypomethylation through mutation of the ICF-gene ZBTB24. Deletion of zebrafish zbtb24 caused a progressive loss of 5mC at pericentromeres and ICF-like phenotypes. Hypomethylation of these repeats triggered derepression of pericentromeric transcripts and activation of an interferon-based innate immune response. Injection of pericentromeric RNA is sufficient to elicit this response in wild-type embryos, and mutation of the MDA5-MAVS dsRNA-sensing machinery blocks the response in mutants. These findings identify activation of the innate immune system as an early consequence of pericentromeric hypomethylation, implicating derepression of pericentromeric transcripts as a trigger of autoimmunity.

Original languageEnglish
Article numbere39658
JournaleLife
Volume7
DOIs
StatePublished - Nov 1 2018

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    Rajshekar, S., Yao, J., Arnold, P. K., Payne, S. G., Zhang, Y., Bowman, T. V., Schmitz, R. J., Edwards, J. R., & Goll, M. (2018). Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome. eLife, 7, [e39658]. https://doi.org/10.7554/eLife.39658