Transcriptomics,Genomics

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Localization of the Rb tumor suppressor in MEFs during reprogramming to iPS and the consequence of Rb loss on the transcriptional profile and histone landscape in these cells


ABSTRACT: The reprogramming of differentiated cells to an embryonic stem cell-like state provides a powerful system to explore fundamental mechanisms of development, including how mammalian cells establish and maintain pluripotency and long-term self-renewal capability. Based on the similarities between embryonic stem cells and cancer cells, we investigated the potential role of the retinoblastoma tumor suppressor and cell cycle regulator RB in the reprogramming of fibroblasts into induced pluripotent stem cells (iPS cells). Herein we demonstrate that loss of RB function leads to both an acceleration of the reprogramming process and the generation of more iPS clones from fibroblasts. This effect is largely due to a restrictive role for RB at the early stages of reprogramming. Surprisingly, however, RB inactivation does not enhance the formation of iPS clones by accelerating the proliferation of cells undergoing reprogramming. Rather, a genome-wide investigation of RB targets indicates that RB binds to regulatory regions of pluripotency genes such as Sox2 and Oct4 and contributes to their full repression in differentiated cells. This effect correlates with the maintenance of a repressive chromatin structure at these loci. Accordingly, Rb-deficient fibroblasts can be reprogrammed into iPS cells even in the absence of exogenous Sox2, which is normally required to initiate reprogramming from fibroblasts. These experiments identify a novel barrier in the reprogramming process, mainly the repression of certain pluripotency genes such as Sox2 by RB, which provides a new link between tumor suppressor mechanisms and cellular reprogramming. RNAseq from MEFs with 2 biological replicates (save CP), Rb ChIPseq from MEFs with 2 biological replicates, Histone H3 modification ChIPseq from MEFs with 1 biological replicate

ORGANISM(S): Mus musculus  

SUBMITTER: Julien Sage  Marius Wernig   Laura L Gorges   Sana Hafeez   Damek Spacek   Dedeepya Vaka   Luis F Batista   Steven E Artandi   Michael S Kareta    

PROVIDER: E-GEOD-40594 | ArrayExpress | 2014-11-13

SECONDARY ACCESSION(S): GSE40594SRP015417PRJNA174435

REPOSITORIES: GEO, ArrayExpress, ENA

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