Section: Research

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Peter Newburger, M.D.

Molecular basis of phagocyte function and myeloid lineage development

Our laboratory currently pursues two major lines of research.

1.  Neutrophils provide the first line of host defense against microbial infections and play a major role in inflammation and tissue damage.  Previous studies of RNA expression in neutrophils have revealed a remarkably vigorous transcriptional response to activation by various stimuli, including changes in expression of a large number of transcription factors.  We are now pursuing a coordinated and comprehensive investigation of the transcribed regions and the regulators of transcriptional activity in developing and mature neutrophils. Studies include the identification of “novel” transcripts using deep sequencing, investigation of transcription factors and their promoter sequence targets, and testing the roles of chromatin structure and remodeling proteins in neutrophil activation and differentiation.  We are particularly interested in the structure and function of long non-coding RNAs in the HOXA cluster. Identification of novel neutrophil-specific genes and regulatory networks could provide new targets for augmentation of host defense in cancer patients and for attenuation of inflammatory disorders.

2.  The human X-linked gene XIST (X-inactive specific transcript) produces a large, non-coding RNA  that is expressed from and accumulates exclusively on the inactive X chromosome, “painting” and silencing the interphase chromosome.    XIST function is not limited to the X chromosome, as shown in balanced (X;autosome) translocations, in which the autosomal material is silenced, creating a functional monosomy.   Genetically engineered human XIST RNA transgenes can also silence an autosome, as shown by studies in mouse embryonic stem cells and cultured human somatic cells.  In collaboration with Dr. Jeanne Lawrence’s laboratory (Dept. of Cell Biology), we are investigating the application of this method to the clinical problem of leukemia in Down syndrome.  Using zinc finger nucleases for site-specific XIST transgene targeting, we are testing the feasibility of XIST-mediated chromosome 21 silencing in human Down syndrome induced pluripotent stem (iPS) cells. We will then determine whether silencing of the trisomic chromosome 21 in Down syndrome iPS cells can correct the hyperproliferative phenotype in iPS-derived hematopoietic progenitor cells.  The eventual goal will be to translate the approach to the prevention or treatment of hematological malignancies in patients with Down syndrome

Keywords: Immunology, Gene Expression

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