# Modeling ICF syndrome in mice: Role of Zbtb24 in DNA methylation and antibody production

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $400,000

## Abstract

The Immunodeficiency, Centromeric instability, and Facial anomalies (ICF) syndrome is a rare autosomal
recessive disorder, with the vast majority of cases carrying mutations in either the DNA methyltransferase gene
DNMT3B (ICF1) or the zinc finger protein gene ZBTB24 (ICF2). A hallmark of ICF syndrome is loss of DNA
methylation in specific genomic regions, which is believed to be the primary defect underlying other phenotypic
abnormalities, including antibody deficiency (hypogammaglobulinemia), facial dysmorphism, and mental
retardation. Patients with ICF syndrome usually die of recurrent infections in early childhood. Although ICF
syndrome was first reported nearly four decades ago, little progress has been made in understanding the
pathogenesis of the disease, largely because of the lack of appropriate in vitro and in vivo models. Modeling
ICF syndrome using Dnmt3b mutant mice has been a challenge, because complete inactivation of Dnmt3b
leads to embryonic lethality and mice carrying ICF-like point mutations fail to recapitulate antibody deficiency.
Preliminary data from the applicant's laboratory revealed that Zbtb24 depletion in mouse embryonic stem cells
(ESCs) results in substantial Dnmt3b downregulation and DNA methylation alterations characteristic of ICF
syndrome and that conditional Zbtb24 deletion in the hematopoietic lineage leads to severe
hypogammaglobulinemia in mice, apparently due to defects in plasma cell differentiation or survival. The
objective of this application is to determine the role of Zbtb24 in the regulation of DNA methylation and
antibody production. The central hypothesis is that Zbtb24, via regulating Dnmt3b expression, controls DNA
methylation, gene expression, and chromatin structure in lymphocyte populations that are important for
antibody production. The applicant proposes to use Zbtb24-deficient ESCs to elucidate the molecular
mechanism by which Zbtb24 regulates Dnmt3b expression and determine the impacts of Zbtb24 deficiency on
DNA methylation, gene expression, and chromatin structure (aim 1). The applicant also proposes to use the
Zbtb24-mutant ICF mouse model to determine the cellular defects involved in antibody deficiency and
elucidate the links between aberrant DNA methylation and the defects in gene expression, chromatin structure
and molecular signaling that contribute to antibody deficiency (aim 2). The project is significant, because
results from the proposed work will not only fundamentally advance mechanistic understanding of ICF
syndrome, but could also shed light on the etiology and defects underlying other antibody deficiency diseases,
including common variable immunodeficiency (CVID). These results will also have general implications in
understanding the role of epigenetic mechanisms in immunity and immunological disorders. The project has
potential translational impact as well, because results from the proposed work could lead to identification of
novel therapeutic strategies for ICF syndrome ...

## Key facts

- **NIH application ID:** 9988347
- **Project number:** 5R01AI121403-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Taiping Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $400,000
- **Award type:** 5
- **Project period:** 2016-09-26 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988347

## Citation

> US National Institutes of Health, RePORTER application 9988347, Modeling ICF syndrome in mice: Role of Zbtb24 in DNA methylation and antibody production (5R01AI121403-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9988347. Licensed CC0.

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