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Genome-wide analysis of telomerase-regulated genes in MLL-AF9 acute myeloid leukemia stem cells (LSCs)

ABSTRACT: Genome-wide transcriptional profiling of purified telomerase deficient (Terc-/-) and WT LSCs was performed in order to gain insights into the mechanisms underlying the susceptibilities of Terc-/- LSCs in vivo. Results provide important information on the response of LSCs to telomerase deficiency, such as telomerase-dependent genes, and dysregulated cellular functions including cell cycle, DNA replication, recombination and repair, altered cellular morphology, cellular function and maintenance, and activated programmed cell death.

ORGANISM(S): Mus musculus

PROVIDER: GSE63241 | GEO | 2014/11/14

SECONDARY ACCESSION(S): PRJNA267086

REPOSITORIES: GEO

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Genome-wide analysis of telomerase-regulated genes in MLL-AF9 acute myeloid leukemia stem cells (LSCs)

Project description:Genome-wide transcriptional profiling of purified telomerase deficient (Terc-/-) and WT LSCs was performed in order to gain insights into the mechanisms underlying the susceptibilities of Terc-/- LSCs in vivo. Results provide important information on the response of LSCs to telomerase deficiency, such as telomerase-dependent genes, and dysregulated cellular functions including cell cycle, DNA replication, recombination and repair, altered cellular morphology, cellular function and maintenance, and activated programmed cell death. Total RNA obtained from G3 Terc-/- LSCs compared to WT LSCs (MLLAF9gfp+, lin-, kit+, Fcgr+) purified from primary recipients at individual disease onset.

2014-11-14 | E-GEOD-63241 | biostudies-arrayexpress

Genome-wide expression analysis of wide-type and PirBTM MLL-AF9 LSCs

Project description:How the stemness of adult stem cells and cancer stem cells is regulated by environmental cues through surface receptors is poorly understood. In this gene expression analysis, we found that, in the mouse MLL-AF9 acute myeloid leukemia (AML) model, a deficiency in intracellular signaling of inhibitory receptor PIR-B resulted in increased differentiation and decreased stemness of leukemia stem cells, revealing that PIR-B supports leukemia development. Our study indicates unexpected functional significance of a classical immune inhibitory receptor in the maintenance of stemness of cancer stem cells. Total RNA obtained from wild-type MLL-AF9 LSCs compared to PirBTM MLL-AF9 LSCs

2012-03-08 | E-GEOD-36329 | biostudies-arrayexpress

Ablation of Telomerase and Ku86

Project description:Transcriptome of murine testis from wild type mice and mice lacking telomerase for three generations (G3-Terc), Ku86 or both telomerase and Ku86. Keywords: ordered

2005-05-12 | GSE2498 | 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

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

Transcription profiling of testis from wild type mice and mice lacking telomerase for three generations (G3-Terc), Ku86 or both telomerase and Ku86 to identify effectors of mammalian telomere dysfunction.

Project description:Transcriptome of murine testis from wild type mice and mice lacking telomerase for three generations (G3-Terc), Ku86 or both telomerase and Ku86.

2007-09-04 | E-GEOD-2498 | 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.

2010-05-10 | GSE21523 | GEO

Disruption of ZC3H15 Compromises Telomere Length Maintenance by Sequestering Telomerase within Cajal bodies

Project description:Telomere homeostasis, crucial for various biological processes, relies on telomerase activity. We identified ZC3H15 as a novel telomerase-interacting protein. Its deletion unexpectedly increased telomerase activity but led to shortened telomeres and cellular senescence. ZC3H15 interacts with telomerase and itself, regulating telomerase activity in an RNA-dependent manner. Proximity labeling showed ZC3H15's interaction with proteins involved in organelle assembly and RNA processes. Loss of ZC3H15 sequestered TERC in the Cajal body, reducing telomerase recruitment to telomeres during S phase. These findings unveil ZC3H15's role in telomere dynamics and cellular senescence, suggesting its potential as a target for cancer therapy or anti-aging interventions.

2024-05-06 | PXD052036 | iProX

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

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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