PUBLICATION

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

Authors

Rajshekar, S., Yao, J., Arnold, P.K., Payne, S.G., Zhang, Y., Bowman, T.V., Schmitz, R.J., Edwards, J.R., Goll, M.

ID

ZDB-PUB-181130-8

Date

2018

Source

eLIFE 7: (Journal)

Registered Authors

Bowman, Teresa, Goll, Mary

Keywords

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

Datasets

GEO:GSE116358, GEO:GSE116359, GEO:GSE116352, GEO:GSE116360

MeSH Terms

Animals
Gene Knockout Techniques
Immunity, Innate
Immunologic Deficiency Syndromes/pathology*
DNA Methylation*
Zebrafish
Centromere*
Disease Models, Animal
Face/abnormalities*
Face/pathology
Interferons/metabolism*

(all 11)

PubMed

30484769 Full text @ Elife

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).

Genes / Markers

Figures

Show all Figures

Expression

Fish	Conditions	Stage	Anatomy	Assay	Figure
zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism	RTPCR	Fig. 3
zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism	RTPCR	Fig. 3
zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism	RTPCR	Fig. 3
zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism	RTPCR	Fig. 6 supplemental 1
zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism	RTPCR	Fig. 3
zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism	RTPCR	Fig. 6 supplemental 1
zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism	RTPCR	Fig. 3
zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism	RTPCR	Fig. 3
zbtb24^mk19/mk19	standard conditions	Days 21-29	whole organism	RTPCR	Fig. 3 supplemental 1
zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism	RTPCR	Fig. 3

1 - 10 of 41

Show

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
ifih1^mk29/mk29; zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism irf7 expression amount, ameliorated	Fig. 6
ifih1^mk29/mk29; zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism stat1b expression amount, ameliorated	Fig. 6
ifih1^mk29/mk29; zbtb24^mk22/mk22	standard conditions	Days 30-44	whole organism irf7 expression amount, ameliorated	Fig. 6
ifih1^mk29/mk29; zbtb24^mk22/mk22	standard conditions	Days 30-44	whole organism stat1b expression amount, ameliorated	Fig. 6
mavs^mk28/mk28; zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism irf7 expression amount, ameliorated	Fig. 4
mavs^mk28/mk28; zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism stat1b expression amount, ameliorated	Fig. 4
myd88^{hu3568/hu3568}; zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism irf7 expression increased amount, abnormal	Fig. 4
myd88^{hu3568/hu3568}; zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism stat1b expression increased amount, abnormal	Fig. 4
sting1^mk30/mk30; zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism irf7 expression increased amount, abnormal	Fig. 4
sting1^mk30/mk30; zbtb24^mk22/mk22	standard conditions	Days 21-29	whole organism stat1b expression increased amount, abnormal	Fig. 4

1 - 10 of 66

Show

Mutations / Transgenics

Allele	Type	Affected Genomic Region
hu3568	Point Mutation	myd88
mk19	Small Deletion	zbtb24
mk22	Indel	zbtb24
mk28	Small Deletion	mavs
mk29	Small Deletion	ifih1
mk30	Small Deletion	sting1
s904	Point Mutation	dnmt1

1 - 7 of 7

Show

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
immunodeficiency-centromeric instability-facial anomalies syndrome	zbtb24^mk22/mk22	standard conditions	TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
ifih1	CRISPR1-ifih1	CRISPR
mavs	CRISPR2-mavs	CRISPR
sting1	CRISPR1-sting1	CRISPR
zbtb24	TALEN1-zbtb24	TALEN
zbtb24	TALEN2-zbtb24	TALEN
zbtb24	TALEN3-zbtb24	TALEN

Fish

Fish
ifih1^mk29/mk29; zbtb24^mk22/mk22
mavs^mk28/mk28; zbtb24^mk22/mk22
myd88^{hu3568/hu3568}; zbtb24^mk22/mk22
sting1^mk30/mk30; zbtb24^mk22/mk22
zbtb24^mk19/mk19
zbtb24^mk22/mk22

Antibodies

Orthology

Gene	Orthology
zbtb24

Engineered Foreign Genes

Mapping

Rajshekar et al., 2018 ZDB-PUB-181130-8 PMID:30484769

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

Rajshekar et al., 2018

ZDB-PUB-181130-8
PMID:30484769