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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE21523 | GEO | 2010/05/10

SECONDARY ACCESSION(S): PRJNA125957

REPOSITORIES: GEO

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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 Ã-galactosidase+ cells and cells exhibiting DNA damage positive for Î³-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. control (WT) and the test (G3 - mTERC-/-) samples

2010-05-27 | E-GEOD-21523 | biostudies-arrayexpress

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

Project description: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.

2016-01-29 | GSE77362 | GEO

A genetic interaction between RAP1 and telomerase reveals an unanticipated role for RAP1 in telomere protection

Project description:RAP1 is one of the components of mammalian shelterin, the capping complex at chromosome ends or telomeres, although its role in telomere protection has remained elusive. RAP1 binds along chromosome arms, where it regulates gene expression and has been shown to function in metabolism control. Telomerase is the enzyme that elongates telomeres and its deficiency causes a premature aging in mice. We describe an unanticipated genetic interaction between RAP1 and telomerase. While RAP1 deficiency alone does not impact in mouse survival, mice lacking both RAP1 and telomerase show a progressive decreased survival with increasing mouse generation as compared to telomerase single mutants. Telomere shortening was more pronounced in Rap1-/- Terc-/- than in Terc-/- counterparts, leading to an earlier onset of DNA damage and its consequent DNA damage response as well as accelerated degenerative pathologies in the intestines. In its turn, telomerase deficiency abolishes RAP1-mediated obesity and liver pathologies. Mouse embryonic fibroblasts with shorten telomeres present less amount of telomere-bound RAP1 but in contrast show higher numbers of RAP1 bound extratelomeric sites genomewide. Absence of RAP1 leads to deregulation of several metabolic pathways, and these changes were more pronounce in cells with short telomeres suggesting that RAP1 release from telomere foci could constitute a coordinated genomic response to telomere shortening. Our findings also demonstrate that although RAP1 is not a key factor in telomere capping under normal conditios, under stress situation such as critical telomere shortening RAP1 exerts an important function for telomere protection and justify its evolutionary conservation as a shelterin component in mammalian cells.

2016-11-16 | GSE79996 | GEO

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

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 3′ 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 3′ oligo-adenylation of TERC would counteract the deleterious effects of PARN mutations. Inhibition of the noncanonical poly(A) polymerase PAP-associated domain–containing 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.

2016-08-02 | GSE81507 | GEO

Genome-wide analysis of TERC occupancy in MRC5 fibroblast cells by ChIRP-seq

Project description:TERC is the core subunit of telomerase which is responsible for adding telomeric sequences to the telomere ends. Besides being the RNA temple of telomerase, TERC is a typical Lnc RNA and ubiquitously expressed in normal somatic cells without telomerase activity. It is very likely that TERC has other, yet to be discovered functions in normal somatic cells independent of telomerase activity. Identifying the genomic occupancy of TERC helps to understand its functional mechanism on chromosomal DNA. Then, we analyzed the genome occupancy of TERC in MRC5 fibroblast cells that is without telomerase activity by ChIRP-seq, and found that there was not apparent enrichment of TERC on telomere sequences in normal somatic cells, but showed a significant enrichment on gene promoters/transcription start sites. This study provides a mechanistic insight of TERC on transcriptional regulation in normal somatic cells.

2022-03-28 | GSE183642 | GEO

Genome-wide omparism of Terc deficient ntESCs

Project description:Haplo-insufficiency of telomerase genes in humans leads to telomere syndromes such as dyskeratosis congenital and idiopathic pulmonary fibrosis. Generation of pluripotent stem cells from telomerase haplo-insufficient donor cells would provide unique opportunities towards the realization of patient-specific stem cell therapies. Recently, pluripotent human embryonic stem cells (ntESCs) have been efficiently achieved by somatic cell nuclear transfer (SCNT). We tested the hypothesis that SCNT could effectively elongate shortening telomeres of telomerase haplo-insufficient cells in the ntESCs using relevant mouse models. Indeed, telomeres of telomerase haplo-insufficient (Terc+/-) mouse cells are elongated in ntESCs. Moreover, ntESCs derived from Terc+/- cells exhibit naïve pluripotency as evidenced by generation of Terc+/-ntESC clone pups by tetraploid embryo complementation (TEC), the most stringent test of naïve pluripotency. These data suggest that SCNT could offer a powerful tool to reprogram telomeres and to discover the factors for robust restoration of telomeres and pluripotency of telomerase haplo-insufficient somatic cells.

2014-11-30 | GSE62692 | GEO

Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells

Project description:Genetic lesions that reduce telomerase cause a range of incurable diseases including dyskeratosis congenita (DC) and pulmonary fibrosis (PF), and restoring telomere length in these patients would be curative. Ectopic expression of telomerase reverse transcriptase (TERT) risks cellular immortalization, and how to target telomerase in stem cells throughout the body remains unclear. Here we describe a successful screen for small molecules that augment TERC, the non-coding telomerase RNA component, and thereby specifically elongate telomeres in stem cells. PAPD5 is a non-canonical polymerase that oligo-adenylates and destabilizes TERC. Using a high-throughput screen we identify BCH001, a specific PAPD5 inhibitor that decreases TERC 3′- oligo(A) tailing and increases telomerase activity and telomere length by thousands of nucleotides in DC patient induced pluripotent stem cells (iPSCs). BCH001 does not result in immortalization or telomere elongation in somatic cells which lack TERT, establishing a favorable safety profile. When human hematopoietic stem and progenitor cells (HSPCs) engineered by CRISPR-Cas9 to carry PARN mutations that cause DC and PF are xenotransplanted into immunodeficient mice, oral treatment with PAPD5 inhibitors rescues TERC 3′-end maturation and telomere length. Our data demonstrate telomere restoration in human stem cells in vivo using small molecules.

2020-04-21 | GSE144986 | GEO

Poly(A)-specific ribonuclease (PARN) mediates 3' end maturation of the telomerase RNA component

Project description:Mutations in the poly(A) ribonuclease (PARN) gene cause telomere diseases including familial idiopathic pulmonary fibrosis (IPF) and dyskeratosis congenita (DC)1,2, but how PARN deficiency impacts telomere maintenance is unclear. Here, using somatic cells and induced pluripotent stem (iPS) cells from DC patients with PARN mutations, we show that PARN is required for the 3′ end maturation of the telomerase RNA component (TERC). Patient cells as well as immortalized cells in which PARN is disrupted show decreased levels of TERC. Deep sequencing of TERC RNA 3′ termini reveals that PARN is required for removal of posttranscriptionally acquired oligo(A) tails that target nuclear RNAs for degradation. Diminished TERC levels and the increased oligo(A) forms of TERC are normalized by restoring PARN, which is limiting for TERC maturation in cells. Our results reveal a novel role for PARN in the biogenesis of TERC, and provide a mechanism linking PARN mutations to telomere diseases. mRNA sequencing of fibroblasts, induced pluripotent stem cells, and 293 cell line.

2015-09-08 | E-GEOD-71709 | biostudies-arrayexpress

Gene expression changes by telomere shortening in human colonic organoids

Project description:Gene expression changes of UC-model organoids derive from human colon indcued by telomere enlongation was assessed by Madecassoside treatemt (telomerase activator). Gene expression changes of human colon organoids induced by telomere shortening was assessd by MST-312 treatment (telomerase inhibitor).

2021-06-24 | GSE175994 | GEO

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