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

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...

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Published in:Human molecular genetics 2016-09, Vol.25 (18), p.4041-4051
Main Authors: Wu, Haoyu, Thijssen, Peter E, de Klerk, Eleonora, Vonk, Kelly K D, Wang, Jun, den Hamer, Bianca, Aytekin, Caner, van der Maarel, Silvère M, Daxinger, Lucia
Format: Article
Language:English
Subjects:
Animals
Codon, Nonsense - genetics
DNA (Cytosine-5-)-Methyltransferases - genetics
DNA Helicases - genetics
DNA Methyltransferase 3B
Face - abnormalities
Face - physiopathology
Female
Gene Expression Regulation, Developmental
Humans
Immunologic Deficiency Syndromes - genetics
Immunologic Deficiency Syndromes - physiopathology
Male
Mice
Mouse Embryonic Stem Cells - metabolism
Nuclear Proteins - biosynthesis
Nuclear Proteins - genetics
Primary Immunodeficiency Diseases
Repressor Proteins - genetics
Transcription, Genetic
Transcriptome - genetics
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddw243