Rao, Shilpa

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2014 - 20152
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  • Publication
    The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins
    (2015-12-01) Li, Ning; Yousefi, Maryam; Nakauka-Ddamba, Angela; Vandivier, Lee; Naqvi, Ammar S; Rao, Shilpa; Tobias, John; Cedeno, Ryan J; Valvezan, Alexander James; Shankar, Sheila; Li, Fan; Klein, Peter S; Parada, Kimberly; Jensen, Shane T; Woo, Dong-Hun; Wang, Shan; Gregory, Brian D; Lengner, Christopher J; Minuesa, Gerard; Y, Katz; Barlowe, Trevor S; Deering, Raquel R; Kharas, Michael G; Yu, Zhengquan
    Members of the Msi family of RNA-binding proteins have recently emerged as potent oncoproteins in a range of malignancies. MSI2 is highly expressed in hematopoietic cancers, where it is required for disease maintenance. In contrast to the hematopoietic system, colorectal cancers can express both Msi family members, MSI1 and MSI2. Here, we demonstrate that, in the intestinal epithelium, Msi1 and Msi2 have analogous oncogenic effects. Further, comparison of Msi1/2-induced gene expression programs and transcriptome-wide analyses of Msi1/2-RNA-binding targets reveal significant functional overlap, including induction of the PDK-Akt-mTORC1 axis. Ultimately, we demonstrate that concomitant loss of function of both MSI family members is sufficient to abrogate the growth of human colorectal cancer cells, and Msi gene deletion inhibits tumorigenesis in several mouse models of intestinal cancer. Our findings demonstrate that MSI1 and MSI2 act as functionally redundant oncoproteins required for the ontogeny of intestinal cancers.
  • Publication
    Paternal Poly (ADP-ribose) Metabolism Modulates Retention of Inheritable Sperm Histones and Early Embryonic Gene Expression
    (2014-05-01) Leu, N. A.; Rao, Shilpa; Ihara, Motomasa; Meyer-Ficca, Mirella L; Gregory, Brian D; Schultz, Richard M; Li, Fan; Zalenskaya, Irina A; Meyer, Ralph G
    To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo.