Global reduction of 5-hydroxymethylcytosine in a FMR1 premutation mice model. B. Yao1, L. Lin1, C. Street1, Z. Zalewski2, J. Galloway2, D. Nelson2, P. Jin1 1) Human Genetics, Emory University, Atlanta, GA; 2) Human and Molecular Genetics, Baylor College of Medicine, Houston, TX.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder, with patients carrying permutation alleles of 55-200 CGG repeats on the FMR1 gene. The cerebella of FXTAS patients usually develop reduced and ectopic Purkinje cells. It has been proposed that the CGG expansion disrupts the balance and availability of RNA-binding proteins, therefore affecting their cellular functions. How this alteration of transcriptional states and epigenetic regulation modulates FXTAS has yet to be explored. DNA 5-hydroxymethylcytosine (5hmC) converted from 5-methylcytosine (5mC) by ten-eleven translocation (TET proteins), has been recently reported. This novel epigenetic mark provides a completely new perspective on the plasticity of 5mC-dependent epigenetic regulation. Here we applied genome-wide profiling of cerebellar 5hmC in a FXTAS mice model (CGG mice) with their Purkinje neurons ectopically expressing 90 CGG repeats. 16 weeks CGG mice showed overall reduced 5hmC levels genome-wide compared to their wildtype littermates. The reduced 5hmC can be readily detected on gene bodies and CpG islands. However, gain-of-5hmC regions have also been observed in repetitive elements such as SINE, LTR and simple repeats. Importantly, in cerebellum, tissue-specific enhancers but not general enhancers showed higher 5hmC levels in CGG mice, implying that 5hmC regulates cerebellum-specific gene expression via manipulating enhancer cytosine modification. Separately mapping wildtype and CGG specific DhMRs (differential 5-hydroxymethylated regions) revealed their highly correlation with neuronal developmental gene ontology terms and functional pathways. Genomic annotation separately identified 6026 wildtype- and 2969 CGG-specific 5hmC-associated genes. Among those, 148 wildtype- or 78 CGG- DhMR associated genes are overlapping with 498 genes that are differentially associated with ribosomes in CGG mice identified by bacTRAP ribosomal profiling when they are in 4 weeks of age. Taken together, our data strongly indicates the functional importance of 5hmC in the etiology of FXTAS, possibly through the regulation of transcription, and shed light on the potential therapeutic interventions.
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