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Cesana, Marcella

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Cesana

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Marcella

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Cesana, Marcella

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2014 - 20163

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Author's Publications: search.filters.isAuthorOfPublication.815fd3c2-5256-41a2-94a2-de84932df4cf

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    The Epithelial-Mesenchymal Transition Factor SNAIL Paradoxically Enhances Reprogramming
    (Elsevier, 2014) Unternaehrer, Juli J.; Zhao, Rui; Kim, Kitai; Cesana, Marcella; Powers, John T.; Ratanasirintrawoot, Sutheera; Onder, Tamer; Shibue, Tsukasa; Weinberg, Robert A.; Daley, George Q.
    Summary Reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs) entails a mesenchymal to epithelial transition (MET). While attempting to dissect the mechanism of MET during reprogramming, we observed that knockdown (KD) of the epithelial-to-mesenchymal transition (EMT) factor SNAI1 (SNAIL) paradoxically reduced, while overexpression enhanced, reprogramming efficiency in human cells and in mouse cells, depending on strain. We observed nuclear localization of SNAI1 at an early stage of fibroblast reprogramming and using mouse fibroblasts expressing a knockin SNAI1-YFP reporter found cells expressing SNAI1 reprogrammed at higher efficiency. We further demonstrated that SNAI1 binds the let-7 promoter, which may play a role in reduced expression of let-7 microRNAs, enforced expression of which, early in the reprogramming process, compromises efficiency. Our data reveal an unexpected role for the EMT factor SNAI1 in reprogramming somatic cells to pluripotency.
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    Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma
    (2016) Powers, John T.; Tsanov, Kaloyan M; Pearson, Daniel; Roels, Frederik; Spina, Catherine S; Ebright, Richard; Seligson, Marc; de Soysa, Yvanka; Cahan, Patrick; Theiβen, Jessica; Tu, Ho-Chou; Han, A Reum; Kurek, Kyle C; LaPier, Grace S; Osborne, Jihan; Ross, Samantha J; Cesana, Marcella; Collins, James; Berthold, Frank; Daley, George
    Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumor suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. However, here we show that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN mRNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN-amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma pathogenesis with broad implications for cancer pathogenesis.
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    Transcriptional and Chromatin Dynamics of Muscle Regeneration after Severe Trauma
    (Elsevier, 2016) Aguilar, Carlos A.; Pop, Ramona; Shcherbina, Anna; Watts, Alain; Matheny, Ronald W.; Cacchiarelli, Davide; Han, Woojin M.; Shin, Eunjung; Nakhai, Shadi A.; Jang, Young C.; Carrigan, Christopher T.; Gifford, Casey A.; Kottke, Melissa A.; Cesana, Marcella; Lee, Jackson; Urso, Maria L.; Meissner, Alexander
    Summary Following injury, adult skeletal muscle undergoes a well-coordinated sequence of molecular and physiological events to promote repair and regeneration. However, a thorough understanding of the in vivo epigenomic and transcriptional mechanisms that control these reparative events is lacking. To address this, we monitored the in vivo dynamics of three histone modifications and coding and noncoding RNA expression throughout the regenerative process in a mouse model of traumatic muscle injury. We first illustrate how both coding and noncoding RNAs in tissues and sorted satellite cells are modified and regulated during various stages after trauma. Next, we use chromatin immunoprecipitation followed by sequencing to evaluate the chromatin state of cis-regulatory elements (promoters and enhancers) and view how these elements evolve and influence various muscle repair and regeneration transcriptional programs. These results provide a comprehensive view of the central factors that regulate muscle regeneration and underscore the multiple levels through which both transcriptional and epigenetic patterns are regulated to enact appropriate repair and regeneration.