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Cell Journal، جلد ۱۶، شماره Suppl ۱، صفحات ۲۸-۲۸
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عنوان انگلیسی Is-28: Epigenetic Regulation of Stem Cells during Reprogramming and Differentiation: Histone Deacetylases and Centrosomes
چکیده انگلیسی مقاله Somatic Cell Nuclear Transfer (SCNT) and Induced pluripotency (iPS) in humans both provide unique patientspecific, disease-bearing pluripotent cell lines (PSCs) important to biomedical investigations, and yet the molecular mechanisms responsible for iPS are virtually unknown. Notwithstanding progress elucidating the roles of transcription factors and chromatin modifications during reprograming, cytoplasmic mediators remain largely unexplored. Here, evidence shows post-translationally modified microtubules (PTM), including mitotic spindle pole centrioles in human pluripotent stem cells (hPSCs), are involved in human iPS derivation. Acetylated a-tubulin antibodies targeting lysine 40 (Ac-Tub) detects subsets of assembled microtubules, including centrioles, in parent human foreskin fibroblast 1 (HFF1) cells. Following HFF1 reprogramming using four ‘Yamanaka’ factors, iPS cells show markedly increased centriolar Ac-Tub, unlike their progeny following in vitro differentiation. Antibodies to HDAC6, a cytoplasmic α-tubulin deacetylase (TDAC), strongly detect HFF1 mitotic centrosomes, but are lost following iPS reprogramming. Interestingly, HDAC6 centrosome labeling is restored after in vitro differentiation. Reduction of HFF1 HDAC6 levels with shRNA demonstrates strong microtubule hyperacetylation, including centrioles, and significantly reduces iPS colony formation. Conversely, HDAC6 over-expression reduces microtubule acetylation without impacting iPS reprogramming. Tubastatin-A (TubA), a chemical HDAC6 inhibitor, also hyperacetylates microtubules, with loss of centriole acetylation above 50 nM. Analogous to HDAC6 shRNA, TubA ≥ 100 nM significant blocks iPS colony formation. Collectively, the role of the cytoplasm and cytoskeleton in mediating reprogramming events, likely downstream from nuclear factors, demonstrates tight cooperation between nuclear dynamics and cytoskeletal plasticity. Perhaps microtubule PTM, like transcriptional regulation, is essential for iPS derivation, identifying an unappreciated example of cytoplasmic post-translational reprogramming. Supported by the US National Institutes of Health.
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نشانی اینترنتی http://celljournal.org/journal/article/abstract/322
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