- Staff Scientist, NIDDK, NIH, 2006-present
- Research Fellow, NIDDK, NIH, 2003-2006
- Visiting Fellow, NIDDK, NIH, 1998-2003
- Project Assistant, National Institute of Immunology, 1997-1998
- Ph.D., Jawaharlal Nehru University, 1997
- M.S., Maharaja Sayajirao University, 1990
- B.S., Mahraja Sayajirao University, 1988
To understand the mechanism of repeat-mediated gene silencing in the Repeat Expansion Diseases and to develop and evaluate strategies to normalize transcription of the affected gene.
Repeat Expansion Diseases (REDs) are a group of human diseases that all arise from an intergenerational increase in the number of repeats in a single, disease-specific tandem array. In a subset of these diseases, large repeat expansions induce an altered chromatin environment at the locus that negatively affects gene expression. For example, expansion of a CGG•CCG-repeat tract in the 5’-untranslated region of the fragile X mental retardation-1 (FMR1) gene causes transcriptional silencing and the loss of encoded protein, FMRP. This results in fragile X syndrome (FXS), the leading form of inherited intellectual disability and the most common monogenic cause of autism. We have shown that the (FMR1) transcript is responsible for recruiting Polycomb Repressive Complex 2 (PRC2) to the 5’ end of the (FMR1) gene and that blocking this recruitment blocks gene silencing.
Expansion of a GAA•TTC-repeat tract in intron 1 of the frataxin (FXN) gene is associated with reduced FXN mRNA and a deficit of frataxin, a mitochondrial protein thought to be involved in the biogenesis of iron-sulfur clusters. This results in Friedreich ataxia (FRDA), a neurodegenerative disorder affecting gait and balance that is also associated with a high incidence of hypertrophic cardiomyopathy and diabetes. We have shown that expansion of the FRDA repeat is associated with elevated DNA methylation in the region flanking the repeat, suggesting that FRDA, like FXS, results from aberrant epigenetic silencing. More recently, we showed that chromatin changes are also associated with the expansion of a GCA•TGC-repeat tract in the 5’-untranslated region of the glutaminase (GLS) gene that causes deficiency of GLS mRNA. This deficiency results in reduced levels of glutamate, the major excitatory neurotransmitter in the brain. The glutamate deficiency in turn results in developmental delay and an early onset progressive ataxia. Because the expansion mutation in these three diseases lies outside of the open reading frame which is otherwise normal, strategies that restore transcription may be therapeutically useful.
Work done in our lab and others have shown that treatment with compounds targeting some of the epigenetic modifications induced by repeat expansion can increase transcript levels in patient-derived cells. Epigenetic modifiers are now in clinical trials or in preclinical development for FRDA. This raises the possibility that such strategies may also be useful in the treatment of FXS and/or GLS deficiency caused by repeat expansion.
Applying our Research
Delineating the mechanism of repeat induced epigenetic changes and its effect on transcription in REDs will help general understanding of the contribution of chromatin modifications in regulating gene expression. In addition, it may help design approaches for restoring transcription to normal levels in some of these REDs.
Need for Further Study
The areas that need further study include mechanisms involved in repeat expansion and the underlying pathology in Repeat Expansion Diseases.
- Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington's Disease.
- Zhao X, Kumari D, Miller CJ, Kim GY, Hayward B, Vitalo AG, Pinto RM, Usdin K.
- J Huntingtons Dis (2021) 10:149-163. Abstract/Full Text
- Molecular analysis of FMR1 alleles for fragile X syndrome diagnosis and patient stratification.
- Kumari D, Usdin K.
- Expert Rev Mol Diagn (2020 Apr) 20:363-365. Abstract/Full Text
Research in Plain Language
Fragile X syndrome is the most common form of inherited intellectual disability. It is caused by the absence of FMRP, a protein important for learning and memory. In order to reduce disease symptoms, I am trying to understand what causes this protein to be absent and how we can reverse or compensate for its absence.