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Cherry, Anne Blanche Cresswell

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Cherry

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Anne Blanche Cresswell

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Cherry, Anne Blanche Cresswell
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    Reprogramming Pediatric Genetic Disorders: Pearson Syndrome, Ring 14 Syndrome, and Fanconi Anemia
    (2014-06-06) Cherry, Anne Blanche Cresswell; Daley, George Quentin; Alt, Fred; Zon, Leonard; Poduri, Annpurna; Mostoslavsky, Gustavo
    The effect of a single genetic mutation can vary greatly between different types of cells. The mutated gene may not be expressed in one tissue but may cause a devastating loss of function in another. To learn about disease mechanisms and generate novel therapies, genetic disorders must be studied in the types of cells where the mutations are most deleterious. Recently, scientists have begun manipulating cellular identity to create the cell types most affected by various genetic diseases. This dissertation describes the experience of generating reprogramming models for three genetic disorders: Ring 14 syndrome, Pearson syndrome, and Fanconi anemia.
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    Chromatin Modifying Enzymes as Modulators of Reprogramming
    (Nature Publishing Group, 2012) Onder, Tamer T.; Kara, Nergis; Sinha, Amit U.; Bernt, Kathrin M.; Mancarci, Ogan. B.; Gupta, Piyush B.; Cherry, Anne Blanche Cresswell; Zhu, Nan; Cahan, Patrick; Unternaehrer, Juli; Lander, Eric; Armstrong, Scott A.; Daley, George
    Generation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming involves global epigenetic remodeling. While several proteins are known to regulate chromatin marks associated with the distinct epigenetic states of cells before and after reprogramming, the role of specific chromatin modifying enzymes in reprogramming remains to be determined. To address how chromatin-modifying proteins influence reprogramming, we used shRNAs to target genes in DNA and histone methylation pathways, and have identified positive and negative modulators of iPSC generation. While inhibition of the core components of the polycomb repressive complex 1 and 2, including the histone 3 lysine 27 methyltransferase Ezh2, reduced reprogramming efficiency, suppression of SUV39H1, YY1, and Dot1L enhanced reprogramming. Specifically, inhibition of the H3K79 histone methyltransferase Dot1L by shRNA or a small molecule accelerated reprogramming, significantly increased the yield of iPSC colonies, and substituted for Klf4 and c-Myc. Inhibition of Dot1L early in the reprogramming process is associated with a marked increase in two alternative factors, Nanog and Lin28, which play essential functional roles in the enhancement of reprogramming. Genome-wide analysis of H3K79me2 distribution revealed that fibroblast-specific genes associated with the epithelial to mesenchymal transition lose H3K79me2 in the initial phases of reprogramming. Dot1L inhibition facilitates the loss of this mark from genes that are fated to be repressed in the pluripotent state. These findings implicate specific chromatin-modifying enzymes as barriers to or facilitators of reprogramming, and demonstrate how modulation of chromatin-modifying enzymes can be exploited to more efficiently generate iPSCs with fewer exogenous transcription factors.