Publication Date:
2010-02-19
Description:
Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues. Patient-specific induced pluripotent stem (iPS) cells represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT). We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3' deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058620/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058620/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Agarwal, Suneet -- Loh, Yuin-Han -- McLoughlin, Erin M -- Huang, Junjiu -- Park, In-Hyun -- Miller, Justine D -- Huo, Hongguang -- Okuka, Maja -- Dos Reis, Rosana Maria -- Loewer, Sabine -- Ng, Huck-Hui -- Keefe, David L -- Goldman, Frederick D -- Klingelhutz, Aloysius J -- Liu, Lin -- Daley, George Q -- DP1 OD000256/OD/NIH HHS/ -- DP1 OD000256-01/OD/NIH HHS/ -- K08 HL089150/HL/NHLBI NIH HHS/ -- K08 HL089150-01A1/HL/NHLBI NIH HHS/ -- K08HL089150/HL/NHLBI NIH HHS/ -- R01 AG027388/AG/NIA NIH HHS/ -- R01 AG027388-01A2/AG/NIA NIH HHS/ -- R01AG0227388/AG/NIA NIH HHS/ -- U01 HL100001/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Mar 11;464(7286):292-6. doi: 10.1038/nature08792. Epub 2010 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Hematology/Oncology, Children's Hospital Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20164838" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Cycle Proteins/genetics
;
Cell Line
;
Cellular Reprogramming/genetics
;
Dyskeratosis Congenita/enzymology/*genetics
;
Gene Expression Regulation, Enzymologic
;
Humans
;
Mice
;
Nuclear Proteins/genetics
;
*Pluripotent Stem Cells/enzymology
;
RNA/genetics/metabolism
;
Sequence Deletion/genetics
;
Telomerase/genetics/metabolism
;
Telomere/*genetics
;
Up-Regulation
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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