Cedeno, Ryan J
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Publication Histone Variant Macroh2a In The Gut And Beyond: A Study Of Intestinal Fortitude(2017-01-01) Cedeno, Ryan JamesEpigenetic factors guide chromatin remodeling during cell state transitions and confer resistance to genotoxic stressors that could induce deleterious transformations. A particularly peculiar component of the epigenome with emerging roles in fine-tuning cell identity and upholding genomic stability is the structural histone variant macroH2A. Relatively little is currently known about macroH2A’s influence on overall cell developmental potency and less still is known about macroH2A’s contributions to adult stem cell identity and function in vivo. In this work, we use induced pluripotent stem cell (iPSC) reprogramming and the murine intestinal stem cell (ISC) system to model macroH2A’s overall impact on cell epigenetic identity from embryo to adult. We manipulated macroH2A content during iPSC reprogramming and concluded that macroH2A removal from somatic chromatin constitutes a mild, but present epigenetic bottleneck to pluripotency acquisition. Using epitope-tagged-macroH2A-expressing cells, we demonstrated that embryonic stem cells (ESCs) display significantly more dynamic macroH2A incorporation and turnover than fibroblasts, particularly proximal to the promoters of highly transcribed genes, concluding that macroH2A is less stably associated with ESC chromatin. In a separate study, we bred macroH2A double germline knockout (DKO) and strain-matched wildtype (WT) mice into reporter strains for ISC subpopulations, enabling us to functionally test active and reserve ISCs during homeostasis and following γ-irradiation injury. We showed that macroH2A DKO intestine is host to elevated numbers of putative reserve ISCs, suggesting that macroH2A may normally limit the size of the reserve ISC pool. We further determined that although macroH2A is unnecessary for intestinal homeostasis, macroH2A strongly bolsters the intestinal regeneration response following irradiative injury by promoting reserve ISC radioresistance. We thus conclude overall that macroH2A imposes a minor resistance to induced pluripotency, limits the size of the reserve ISC pool in adult mice and finally upholds genomic stability by providing resistance to genotoxic stress in vivo.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, ZhengquanMembers 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.