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Expression data between WT and G3/4 Terc KO mouse ESCs during differentiation

ABSTRACT: Mammalian telomeres are formed by tandem repeats of the TTAGGG sequence, and shorten with each round of cell division in the absence of telomerase. Telomere shortening and dysfunction has been implicated in the pathology of several age-related diseases and premature ageing syndromes. Telomerase is important for telomere length maintenance. Telomerase RNA component, also known as TERC, is a component of telomerase. Terc knockout leads to telomerase deficiency and telomere shortening. Heterozygous telomerase-deficient (Terc+/-) mice were housed and bred for homozygous generation. ESC lines were generated with high efficiency from wild-type (WT, Terc+/+), heterozygous (Het, Terc+/-) and early- to late-generation (G1, G3 and G4) Terc-/- mouse blastocysts. Telomeres were shorter in Terc+/- ES cells than in WT ES cells, and further shortened from G1 to G4 Terc-/- ES cells. We took advantage of ES cell lines with various telomere lengths to investigate roles of telomere length on differentiation capacity of ES cells. We found that telomere length, but not telomerase activity, is required for differentiation of ES cells into epidermis. We performed microarray analysis to investigate differential gene expression profile at genome-wide levels between WT and G3/G4 Terc-/- (KO) mouse ES cells and during differentiation in vitro of WT and G4 Terc-/- mouse ES cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE77362 | GEO | 2016/01/29

SECONDARY ACCESSION(S): PRJNA310140

REPOSITORIES: GEO

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Differential gene expression profiles of long bones of telomerase deficient mice (G3-mTERC-/-)

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Genome-wide omparism of Terc deficient ntESCs

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Alleviation of telomere dysfunction and mitochondria defects of telomerase deficient somatic cells by reprogramming

Project description:Somatic cell nuclear transfer (SCNT) and induced pluripotent stem cells (iPSCs) represent two major approaches for somatic cell reprogramming. However, little attention has been paid to the ability of these two strategies in rejuvenating cells from donors with aging associated syndrome. Here, we utilized telomerase deficient (Terc-/-) mice to probe this question. SCNT-derived embryonic stem cells (ntESCs) and iPSCs were successfully derived from second generation (G2) and third generation (G3) of Terc-/- mice, and ntESCs showed better differentiation potential and self-renewal ability. Telomeres lengthened extensively in cloned embryos while remained or slightly increased in the process of iPSCs induction. Furthermore, G3 ntESCs exhibited improvement of telomere capping function as evidenced by decreased signal free ends and chromosome end-to-end fusion events. In contrast, there was a further decline of telomere capping function in G3 iPSCs. In addition to telomere dysfunction, mitochondria function was severely impaired in G3 iPSCs as evidenced by oxygen consumption rate (OCR) decline, reactive oxygen species (ROS) accumulation and dramatically increased mitochondria genome mutations while these deficiencies were greatly mitigated in G3 ntESCs. Our data proved the principle that SCNT-mediated reprogramming appears more superior than transcription factors induced reprogramming in terms of the resetting of telomere quality and mitochondria function, and thus, providing valuable information for further improvement of transcription factors mediated reprogramming. We compared the gene expression profile of G3 Terc-/- ntES and G3 Terc-/- iPS. Three biological repeats were included for each cell line.

2013-11-11 | E-GEOD-46860 | biostudies-arrayexpress

Differential gene expression profiles of long bones of telomerase deficient mice (G3-mTERC-/-)

Project description:Telomere shortening due to telomerase deficiency leads to accelerated senescence of human skeletal (mesenchymal) stem cells (MSC) in vitro. In order to study the role of telomere shortening in vivo, we studied the phenotype of telomerase deficient mice caused by absence of telomerase RNA component (TERC-/-). TERC-/- exhibited accelerated age-related bone loss starting at 3 months of age and during 12 months follow up. Bone histomorphometry revealed decreased mineralized surface and bone formation rate as well as increased osteoclast number and size in TERC-/-. Also, serum total deoxy-pyridinoline (tDPD) was increased in TERC-/-. MSC isolated from TERC-/- exhibited intrinsic defects with reduced total number, lower proliferation rate, decreased expression of osteoblastic (OB) differentiation markers and formed less in vivo ectopic bone compared to WT cells. The TERC-/--MSC cultures accumulated a larger proportion of senescent ß-galactosidase+ cells and cells exhibiting DNA damage positive for γ-H2AX. Micro-array analysis of bones of TERC-/- and WT revealed significant over-expression of a large number of pro-inflammatory genes and signaling pathways in TERC-/- known to control osteoclast (OC) differentiation. In accordance with that, serum from TERC-/- enhanced OC formation in control bone marrow cultures. Our data demonstrate two mechanisms for age-related bone loss caused by telomerase deficiency: intrinsic osteoblastic defects and creation of pro-inflammatory osteoclast-activating microenvironment. Approaches for re-telomerization of MSC may provide a novel approach for abolishing age-related bone loss.

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Post-transcriptional manipulation of TERC reverses molecular hallmarks of telomere disease

Project description:The telomerase RNA component (TERC) is a critical determinant of cellular self renewal. Poly(A)-specific ribonuclease (PARN) is required for post-transcriptional maturation of TERC. PARN mutations lead to incomplete 3â² end processing and increased destruction of nascent TERC RNA transcripts, resulting in telomerase deficiency and telomere diseases. Here, we determined that overexpression of TERC increased telomere length in PARN-deficient cells and hypothesized that decreasing post-transcriptional 3â² oligo-adenylation of TERC would counteract the deleterious effects of PARN mutations. Inhibition of the noncanonical poly(A) polymerase PAP-associated domainâcontaining 5 (PAPD5) increased TERC levels in PARN-mutant patient cells. PAPD5 inhibition was also associated with increases in TERC stability, telomerase activity, and telomere elongation. Our results demonstrate that manipulating post-transcriptional regulatory pathways may be a potential strategy to reverse the molecular hallmarks of telomere disease. mRNA sequencing of induced pluripotent stem cells and 293 cell line.

2016-08-02 | E-GEOD-81507 | biostudies-arrayexpress

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