Zbtb24 binding protects promoter activity by antagonizing DNA methylation in mESCs

Hao, Wu; Ds, Leon Granado; Vukić, Maja; Kk, Vonk; Breukel, Cor; Chouaref, Jihed; Laros, Jeroen F. J.; Daxinger, Lucia

doi:10.1101/858662

Cited by 2 publications

(2 citation statements)

References 67 publications

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“…Altogether, as inferred from ZBTB24 LOF, ZBTB24 does not seem to be directly involved in the DNAme establishment step for a large proportion of the genome. However, our methylome highlights potential role of ZBTB24 in the protection of some of its main genomic targets against DNAme gain during development (37).…”

Section: Resultsmentioning

confidence: 90%

ZBTB24 is a conserved multifaceted transcription factor at genes and centromeres that governs the DNA methylation state and expression of satellite repeats

Grillo,

Boyarchuk,

Mihic

et al. 2023

Preprint

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Since its discovery as an Immunodeficiency with Centromeric instability and Facial anomalies syndrome-causative gene, ZBTB24 has emerged as a key player in DNA methylation, immunity and development. By extensively analyzing ZBTB24 genomic functions in ICF-relevant mouse and human cellular models, we revealed here its multiple facets as a transcription factor, with key roles in immune response-related genes expression and also in early embryonic development. Using a constitutive Zbtb24 ICF-like mutant and an auxin-inducible degron system in mouse embryonic stem cells, we showed that ZBTB24 is recruited to centromeric satellite DNA where it is required to establish the correct DNA methylation patterns through the recruitment of DNMT3B. Thus, our results further revealed an essential role for ZBTB24 at human and mouse centromeric satellite arrays, as a transcriptional repressor. Together, we unveiled unprecedented functions of ZBTB24 at human and mouse centromeres by directly controlling DNA methylation and transcription of the underlying tandem satellite repeats.

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Section: Resultsmentioning

confidence: 90%

ZBTB24 is a conserved multifaceted transcription factor at genes and centromeres that governs the DNA methylation state and expression of satellite repeats

Grillo,

Boyarchuk,

Mihic

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…These genes are direct targets of ZBTB24 and were transcriptionally downregulated in ZBTB24-deficient LCLs and in ZBTB24-mutant mESCs (11,14). Several studies indicate that ZBTB24 binding protects the promoter of these genes from DNMT3B-mediated methylation and gene silencing (41). Whether ZBTB24 directly influences DNA methylation at gene promoters is still unclear.…”

Section: Discussionmentioning

confidence: 99%

A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency

Lullo,

Cecere,

Batti

et al. 2024

Preprint

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Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome is a rare genetic disorder characterized by variable immunodeficiency. More than half of the affected individuals show mild to severe intellectual disability at early onset. This disorder is genetically heterogeneous and ZBTB24 is the causative gene of the subtype 2, accounting for about 30% of the ICF cases. ZBTB24 is a multifaceted transcription factor belonging to the Zinc-finger and BTB domain-containing protein family, which are key regulators of developmental processes. Aberrant DNA methylation is the main molecular hallmark of ICF syndrome. The functional link between ZBTB24 deficiency and DNA methylation errors is still elusive. Here, we generated a novel ICF2 disease model by deriving induced pluripotent stem cells (iPSCs) from peripheral CD34+-blood cells of a patient homozygous for the p.Cys408Gly mutation, the most frequent missense mutation in ICF2 patients and which is associated with a broad clinical spectrum. The mutation affects a conserved cysteine of the ZBTB24 zinc-finger domain, perturbing its function as transcriptional activator. ICF2-iPSCs recapitulate the methylation defects associated with ZBTB24 deficiency, including centromeric hypomethylation. We validated that the mutated ZBTB24 protein loses its ability to directly activate expression of CDCA7 and other target genes in the patient-derived iPSCs. Upon hematopoietic differentiation, ICF2-iPSCs showed decreased vitality and a lower percentage of CD34+/CD43+/CD45+ progenitors. Overall, the ICF2-iPSC model is highly relevant to explore the role of ZBTB24 in DNA methylation homeostasis and provides a tool to investigate the early molecular events linking ZBTB24 deficiency to the ICF2 clinical phenotype.

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Zbtb24 binding protects promoter activity by antagonizing DNA methylation in mESCs

Cited by 2 publications

References 67 publications

ZBTB24 is a conserved multifaceted transcription factor at genes and centromeres that governs the DNA methylation state and expression of satellite repeats

ZBTB24 is a conserved multifaceted transcription factor at genes and centromeres that governs the DNA methylation state and expression of satellite repeats

A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency

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