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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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).

Original languageEnglish (US)
JournaleLife
Volume7
DOIs
StatePublished - Nov 28 2018

Fingerprint

5-Methylcytosine
Centromere
Interferons
Animals
Animal Models
Chemical activation
Mutation
Peer Review
Immune system
Zebrafish
Autoimmunity
Innate Immunity
Machinery
Immune System
Embryonic Structures
Genes
Satellites
RNA
Phenotype
Injections

Keywords

  • chromosomes
  • DNA methylation
  • gene expression
  • ICF Syndrome
  • interferon response
  • pericentromeres
  • zebrafish

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome. / Rajshekar, Srivarsha; Yao, Jun; Arnold, Paige K.; Payne, Sara G.; Zhang, Yinwen; Bowman, Teresa V.; Schmitz, Robert J.; Edwards, John R.; Goll, Mary.

In: eLife, Vol. 7, 28.11.2018.

Research output: Contribution to journalArticle

Rajshekar, S, Yao, J, Arnold, PK, Payne, SG, Zhang, Y, Bowman, TV, Schmitz, RJ, Edwards, JR & Goll, M 2018, 'Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome', eLife, vol. 7. https://doi.org/10.7554/eLife.39658
Rajshekar, Srivarsha ; Yao, Jun ; Arnold, Paige K. ; Payne, Sara G. ; Zhang, Yinwen ; Bowman, Teresa V. ; Schmitz, Robert J. ; Edwards, John R. ; Goll, Mary. / Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome. In: eLife. 2018 ; Vol. 7.
@article{b5028cf81c4c4cb1a753b5163711794b,
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).",
keywords = "chromosomes, DNA methylation, gene expression, ICF Syndrome, interferon response, pericentromeres, zebrafish",
author = "Srivarsha Rajshekar and Jun Yao and Arnold, {Paige K.} and Payne, {Sara G.} and Yinwen Zhang and Bowman, {Teresa V.} and Schmitz, {Robert J.} and Edwards, {John R.} and Mary Goll",
year = "2018",
month = "11",
day = "28",
doi = "10.7554/eLife.39658",
language = "English (US)",
volume = "7",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome

AU - Rajshekar, Srivarsha

AU - Yao, Jun

AU - Arnold, Paige K.

AU - Payne, Sara G.

AU - Zhang, Yinwen

AU - Bowman, Teresa V.

AU - Schmitz, Robert J.

AU - Edwards, John R.

AU - Goll, Mary

PY - 2018/11/28

Y1 - 2018/11/28

N2 - 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).

AB - 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).

KW - chromosomes

KW - DNA methylation

KW - gene expression

KW - ICF Syndrome

KW - interferon response

KW - pericentromeres

KW - zebrafish

UR - http://www.scopus.com/inward/record.url?scp=85057216146&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057216146&partnerID=8YFLogxK

U2 - 10.7554/eLife.39658

DO - 10.7554/eLife.39658

M3 - Article

VL - 7

JO - eLife

JF - eLife

SN - 2050-084X

ER -