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Daman Kumari, Ph.D.

Photo of Daman Kumari
Scientific Focus Areas: Cell Biology, Chromosome Biology, Molecular Biology and Biochemistry, RNA Biology, Stem Cell Biology

Professional Experience

  • 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, 1990
  • B.S., Mahraja Sayajirao University, 1988

Research Goal

The ultimate goal of my research is to develop rational therapies for FXS.

Current Research

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the most common known cause of autism. FXS belongs to the category of human diseases classified as Repeat Expansion Disorders (REDs). This group of disorders is caused by the expansion of a tandem array of a simple repeat tract in a single specific gene. FXS is caused by the expansion of a CGG-repeat tract in the 5’-UTR of the FMR1 gene. Expansion of the CGG-repeats causes gene silencing by heterochromatin formation and results in the absence of its protein product, FMRP. Repeat-mediated chromatin changes are also seen in other REDs, suggesting a common underlying mechanism.

There is no cure or effective treatment for FXS. Restoring FMR1 expression is a potential therapeutic approach for FXS. The main goal of my current research is to delineate the mechanisms involved in the repeat-mediated FMR1 gene silencing which will allow us to design treatment strategies based on gene reactivation. While demethylation induced by 5-azadeoxycytidine (AZA) treatment can partially restore FMR1 gene expression in FXS cells, the gene is switched off once the drug is removed. We have identified a key step in the gene silencing process that can be targeted for sustained expression of the reactivated alleles. We have shown that the FMR1 mRNA recruits polycomb repressive complex 2 (PRC2) to the reactivated FMR1 gene in AZA treated FXS cells, perhaps via its ability to form an RNA:DNA hybrid. Furthermore, treatment with small molecules that inhibit PRC2 activity or PRC2 binding to FMR1 mRNA results in sustained expression of the reactivated FMR1 gene in FXS patient cells. Our data establish the importance of PRC2 for FMR1 gene silencing and suggest gene-specific strategies for the long term expression of the reactivated FMR1 gene in FXS. We are currently designing and testing these approaches.

Applying our Research

FXS-related disorders are debilitating disorders without any effective treatment or cure. Understanding the molecular mechanisms involved in the pathology of FXS will help in designing rational therapeutic approaches for fragile X syndrome patients.

Need for Further Study

The areas that need further study include mechanisms involved in the expansion of CGG-repeats, the role of expanded CGG-repeats in FMR1 gene silencing, and the functions of the FMR1 gene product, FMRP.

Select Publications

CGG-repeat dynamics and FMR1 gene silencing in fragile X syndrome stem cells and stem cell-derived neurons.
Zhou Y, Kumari D, Sciascia N, Usdin K.
Mol Autism (2016) 7:42. Abstract/Full Text
Sustained expression of FMR1 mRNA from reactivated fragile X syndrome alleles after treatment with small molecules that prevent trimethylation of H3K27.
Kumari D, Usdin K.
Hum Mol Genet (2016 Sep 1) 25:3689-3698. Abstract/Full Text
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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.