Polycomb Group Complexes Are Recruited to Reactivated FMR1 Alleles in Fragile X Syndrome in Response to FMR1 Transcription

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2014 Jul 25

PMID 25055869

Citations 25

Authors

Daman Kumari

Karen Usdin

Affiliations

Soon will be listed here.

Abstract

The FMR1 gene is subject to repeat mediated-gene silencing when the CGG-repeat tract in the 5' UTR exceeds 200 repeat units. This results in Fragile X syndrome, the most common heritable cause of intellectual disability and a major cause of autism spectrum disorders. The mechanism of gene silencing is not fully understood, and efforts to reverse this gene silencing have had limited success. Here, we show that the level of trimethylation of histone H3 on lysine 27, a hallmark of the activity of EZH2, a component of repressive Polycomb Group (PcG) complexes like PRC2, is increased on reactivation of the silenced allele by either the DNA demethylating agent 5-azadeoxycytidine or the SIRT1 inhibitor splitomicin. The level of H3K27me3 increases and decreases in parallel with the FMR1 mRNA level. Furthermore, reducing the levels of the FMR1 mRNA reduces the accumulation of H3K27me3. This suggests a model for FMR1 gene silencing in which the FMR1 mRNA generated from the reactivated allele acts in cis to repress its own transcription via the recruitment of PcG complexes to the FMR1 locus.

Citing Articles

Intersection of the fragile X-related disorders and the DNA damage response.

Kumari D, Grant-Bier J, Kadyrov F, Usdin K DNA Repair (Amst). 2024; 144:103785.

PMID: 39549538 PMC: 11789500. DOI: 10.1016/j.dnarep.2024.103785.

Toward understanding the role of genomic repeat elements in neurodegenerative diseases.

An Z, Jiang A, Chen J Neural Regen Res. 2024; 20(3):646-659.

PMID: 38886931 PMC: 11433896. DOI: 10.4103/NRR.NRR-D-23-01568.

EZH2 inhibition reactivates epigenetically silenced and normalizes molecular and electrophysiological abnormalities in fragile X syndrome neurons.

Fang M, Deibler S, Krishnamurthy P, Wang F, Rodriguez P, Banday S Front Neurosci. 2024; 18:1348478.

PMID: 38449737 PMC: 10915284. DOI: 10.3389/fnins.2024.1348478.

The fragile X locus is prone to spontaneous DNA damage that is preferentially repaired by nonhomologous end-joining to preserve genome integrity.

Kumari D, Lokanga R, McCann C, Ried T, Usdin K iScience. 2024; 27(2):108814.

PMID: 38303711 PMC: 10831274. DOI: 10.1016/j.isci.2024.108814.

Methylation across the central dogma in health and diseases: new therapeutic strategies.

Liu R, Zhao E, Yu H, Yuan C, Abbas M, Cui H Signal Transduct Target Ther. 2023; 8(1):310.

PMID: 37620312 PMC: 10449936. DOI: 10.1038/s41392-023-01528-y.

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