Epigenetic profiling linked to multisystem inflammatory syndrome in children (MIS-C): A multicenter, retrospective study
Related Experiment Video
Updated: Sep 6, 2025
Rapid Fractionation and Isolation of Whole Blood Components in Samples Obtained from a Community-based Setting
Published on: November 30, 2015
Veronica Davalos1, Carlos A García-Prieto1,2, Gerardo Ferrer1,3
1Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain.
Insights
DNA methylation changes are linked to multisystem inflammatory syndrome in children (MIS-C). This epigenetic signature, EPIMISC, may offer new therapeutic targets for MIS-C and similar inflammatory conditions.
Area of Science:
- Epigenetics
- Immunology
- Pediatric Infectious Diseases
Background:
- Most children infected with SARS-CoV-2 develop mild or no symptoms.
- A subset of pediatric patients develop severe multisystem inflammatory syndrome in children (MIS-C).
- Epigenetic mechanisms, particularly DNA methylation, are crucial in regulating immune responses and viral activity.
Purpose of the Study:
- To investigate DNA methylation alterations associated with MIS-C.
- To identify specific CpG loci and genes involved in MIS-C pathogenesis.
- To develop an epigenetic signature for MIS-C diagnosis.
Main Methods:
- Analyzed DNA methylation in peripheral blood samples from 43 MIS-C patients and control groups.
- Utilized a genome-wide interrogation of 850,000 CpG sites.
- Employed discovery and validation cohorts balanced for demographic factors.
Main Results:
- Identified 33 CpG loci associated with MIS-C, with 18 located within genes.
- Highlighted ZEB2, SH2D1B, VWA8, HLA-DRB1, CUL2, and AIM2 as top candidate genes.
- Developed an epigenetic signature (EPIMISC) for MIS-C, also found in Kawasaki disease patients.
Conclusions:
- Characterized DNA methylation loci associated with MIS-C diagnosis.
- Identified genes potentially contributing to the exaggerated inflammatory response in MIS-C.
- The EPIMISC signature may provide novel therapeutic targets for MIS-C.
Background:
Most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain asymptomatic or develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients develop a severe clinical condition, multisystem inflammatory syndrome in children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C.
Methods:
Peripheral blood samples were recruited from 43 confirmed MIS-C patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MIS-C = 28) cohorts, and balanced for age, gender and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants.
Findings:
The DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2. The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with a possible viral trigger, that shares many of the clinical features of MIS-C.
Interpretation:
We have characterized DNA methylation loci that are associated with MIS-C diagnosis. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder.
Funding:
Unstoppable campaign of Josep Carreras Leukaemia Foundation, Fundació La Marató de TV3, Cellex Foundation and CERCA Programme/Generalitat de Catalunya.
