Converging disease genes in ICF syndrome: ZBTB24 controls expression of CDCA7 in mammals.

Abstract

For genetically heterogeneous diseases a better understanding of how the underlying gene defects are functionally interconnected will be important for dissecting disease etiology. The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome is a chromatin disorder characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS Here, we generated a Zbtb24 BTB domain deletion mouse and found that loss of functional Zbtb24 leads to early embryonic lethality. Transcriptome analysis identified Cdca7 as the top down-regulated gene in Zbtb24 homozygous mutant mESCs, which can be restored by ectopic ZBTB24 expression. We further demonstrate enrichment of ZBTB24 at the CDCA7 promoter suggesting that ZBTB24 can function as a transcription factor directly controlling Cdca7 expression. Finally, we show that this regulation is conserved between species and that CDCA7 levels are reduced in patients carrying ZBTB24 nonsense mutations. Together, our findings demonstrate convergence of the two ICF genes ZBTB24 and CDCA7 at the level of transcription.

• Authors: Haoyu Wu, Peter E Thijssen, Eleonora de Klerk, Kelly K D Vonk, Jun Wang, Bianca den Hamer, Caner Aytekin, Silvère M van der Maarel, Lucia Daxinger
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 25 Issue 18 Pg. 4041-4051 (09 15 2016) ISSN: 1460-2083 [Electronic] England
• PMID: 27466202 (Publication Type: Journal Article)
• Copyright: © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• CDCA7 protein, human
• Codon, Nonsense
• Nuclear Proteins
• Repressor Proteins
• ZBTB24 protein, human
• DNA (Cytosine-5-)-Methyltransferases
• DNA Helicases
• HELLS protein, human

Topics

• Animals
• Codon, Nonsense (genetics)
• DNA (Cytosine-5-)-Methyltransferases (genetics)
• DNA Helicases (genetics)
• Face (abnormalities, physiopathology)
• Female
• Gene Expression Regulation, Developmental
• Humans
• Immunologic Deficiency Syndromes (genetics, physiopathology)
• Male
• Mice
• Mouse Embryonic Stem Cells (metabolism)
• Nuclear Proteins (biosynthesis, genetics)
• Primary Immunodeficiency Diseases
• Repressor Proteins (genetics)
• Transcription, Genetic
• Transcriptome (genetics)
• DNA Methyltransferase 3B