Rxivist logo

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

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

Posted 23 Aug 2018
bioRxiv DOI: 10.1101/396671 (published DOI: 10.7554/elife.39658)

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.

Download data

  • Downloaded 691 times
  • Download rankings, all-time:
    • Site-wide: 50,395
    • In molecular biology: 1,424
  • Year to date:
    • Site-wide: 114,635
  • Since beginning of last month:
    • Site-wide: 151,661

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide