PgmNr Z6111: New insights into the role of DNA methylation in development and disease from a zebrafish model of ICF syndrome.

Authors:
S. Rajshekar 1,2 ; M. G. Goll 1


Institutes
1) Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2) Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA.


Abstract:

The modified base, 5-methylcytosine (5mC) is enriched at repetitive sequences such as satellite repeats that are located in the vicinity of centromeres. Loss of methylation at these repeats correlates with chromosomal instability and is detected in many cancers and the rare genetic disease Immunodeficiency, Centromeric instability and Facial abnormalities (ICF) syndrome. ZBTB24 is mutated in ICF syndrome Type-2. However, the function of this gene is unknown and animal models have not been described. To understand how ZBTB24 regulates DNA methylation near centromeres and to determine how centromeric hypomethylation contributes to disease pathology, we have developed a zebrafish model for ICF syndrome by generating loss of function mutations in the zebrafish ortholog of ZBTB24 using TAL Effector Nucleases (TALENs). Zbtb24 mutant zebrafish recapitulate features characteristic to ICF patients including distinct cranio-facial anomalies, slow growth and reduced lifespan. We demonstrate that zbtb24 mutation results in a progressive, rather than acute, loss of 5mC at satellite repeats and that this hypomethylation correlates tightly with the onset of phenotypic abnormalities. Intriguingly, we detect an inflammatory RNA signature in zbtb24 mutants prior to the onset of disease phenotypes. This observation suggests the presence of an endogenous inflammation based surveillance system that detects loss of centromere DNA methylation. We propose that during normal development this system protects against malignancy by eliminating affected cells before they accumulate substantial DNA damage.



ZFIN Genetics Index
1. zbtb24