Background: Fragile X mental retardation syndrome (FXS) is the most common heritable cause of intellectual disability and the most common known cause of autism. Other symptoms of FXS include depression, sensory processing deficits, aggressive behavior, connective tissue problems and digestive difficulties. This disorder arises when the number of CGG-repeats in the 5 UTR of the FMR1 gene exceeds 200. Such alleles become silenced. This results in a deficiency of the protein product of this gene, FMRP, which is involved in the regulation of translation of a subset of mRNAs. The FMRP deficiency in brain results in aberrant dendritic spine morphology and a defective response to synaptic activation. The mechanism of gene silencing is unknown. Progress report: We have previously identified a number of steps in the gene silencing process including some that precede DNA methylation and some that occur very late in the silencing process (Biacsi, Kumari and Usdin, 2008). One of the late steps in FX gene silencing turns out to be the deacetylation of histone H4 on lysine 16, a step we showed to be carried out by SIRT1, a class III histone deacetylase. We have shown that inhibiting SIRT1 enables gene reactivation (Biacsi, Kumari and Usdin, 2008). Unlike the inhibition of DNA methylation which requires replication to be effective, SIRT1 inhibition does not. Thus it may be useful in cells like neurons where the effect of gene silencing is most apparent. More recently we have shown that the silenced allele is associated with both marks of facultative and constitutive heterochromatin (Kumari, Biacsi and Usdin, 2010). The constitutive heterochromatin marks have a relatively restricted distribution on the 5 end of the gene with the highest level of these marks being in the vicinity of the repeat. This indicates that the trigger for FMR1 gene silencing may be intrinsic to the repeat. This provides clues as to what the trigger for gene silencing may be. The marks of facultative heterochromatin have a more broad distribution across the 5'end of the gene. We have found that both normal and patient alleles have a heterochromatin block upstream of the FMR1 promoter that contains these 2 histone marks but not the marks of constitutive heterochromatin. It may be that the heterochromatic changes initiated by the repeat trigger the loss of function of a boundary element located in this region. This in turn allows the spread of the facultative heterochromatin marks into the FMR1 gene. This may in essence introduce a second set of repressive heterochromatin marks that act to reinforce gene silencing.

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Hayward, Bruce E; Usdin, Karen (2017) Improved Assays for AGG Interruptions in Fragile X Premutation Carriers. J Mol Diagn 19:828-835
Hayward, Bruce E; Kumari, Daman; Usdin, Karen (2017) Recent advances in assays for the fragile X-related disorders. Hum Genet 136:1313-1327
Zhou, Yifan; Kumari, Daman; Sciascia, Nicholas et al. (2016) CGG-repeat dynamics and FMR1 gene silencing in fragile X syndrome stem cells and stem cell-derived neurons. Mol Autism 7:42
Hayward, Bruce E; Zhou, Yifan; Kumari, Daman et al. (2016) A Set of Assays for the Comprehensive Analysis of FMR1 Alleles in the Fragile X-Related Disorders. J Mol Diagn 18:762-774
Conca Dioguardi, Carola; Uslu, Bahar; Haynes, Monique et al. (2016) Granulosa cell and oocyte mitochondrial abnormalities in a mouse model of fragile X primary ovarian insufficiency. Mol Hum Reprod 22:384-96
Kumari, Daman; Usdin, Karen (2016) Sustained expression of FMR1 mRNA from reactivated fragile X syndrome alleles after treatment with small molecules that prevent trimethylation of H3K27. Hum Mol Genet 25:3689-3698
Kumari, Daman; Swaroop, Manju; Southall, Noel et al. (2015) High-Throughput Screening to Identify Compounds That Increase Fragile X Mental Retardation Protein Expression in Neural Stem Cells Differentiated From Fragile X Syndrome Patient-Derived Induced Pluripotent Stem Cells. Stem Cells Transl Med 4:800-8
Usdin, Karen; Kumari, Daman (2015) Repeat-mediated epigenetic dysregulation of the FMR1 gene in the fragile X-related disorders. Front Genet 6:192
Kumari, Daman; Bhattacharya, Aditi; Nadel, Jeffrey et al. (2014) Identification of fragile X syndrome specific molecular markers in human fibroblasts: a useful model to test the efficacy of therapeutic drugs. Hum Mutat 35:1485-94
Sellier, Chantal; Usdin, Karen; Pastori, Chiara et al. (2014) The multiple molecular facets of fragile X-associated tremor/ataxia syndrome. J Neurodev Disord 6:23

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