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


Authors: Rajshekar, S.; Yao, J.; Arnold, P. K.; Payne, S. G.; Zhang, Y.; Bowman, T. V.; Schmitz, R. J.; Edwards, J. R.; Goll, M.
Article Title: Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome
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. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter). © 2018, Rajshekar et al.
Keywords: gene expression; dna methylation; chromosomes; zebrafish; interferon response; icf syndrome; pericentromeres
Journal Title: eLife
Volume: 7
ISSN: 2050-084X
Publisher: eLife Sciences Publications Ltd.  
Date Published: 2018-11-28
Start Page: e39658
Language: English
DOI: 10.7554/eLife.39658
PROVIDER: scopus c2 - 30484769
PMCID: PMC6261255
PUBMED: 30484769
DOI/URL:
Notes: Elife -- Export Date: 2 January 2019 -- Article -- Source: Scopus C2 - 30484769
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MSK Authors
  1. Mary Grace Goll
    9 Goll
  2. Paige Krystin Arnold
    2 Arnold
  3. Jun Yao
    1 Yao