Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA278084 | ENA |
REPOSITORIES: ENA
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Project description:Patients with dyskeratosis congenita (DC) and related telomeropathies resulting from premature telomere dysfunction suffer from multi-organ failure. In the liver, DC patients present with nodular hyperplasia and cirrhosis. We model DC liver pathologies using isogenic human induced pluripotent stem (iPS) cells harboring a causal DC mutation in DKC1, or a clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-corrected control allele. Differentiation of these iPS cells into hepatocytes or hepatic stellate cells reveals a dominant phenotype in the parenchyma. Generation of genotype admixed hepatostellate organoids indicates that DC hepatocytes elicit a pathogenic hyperplastic response in stellate cells independent of stellate cell genotype. Phenotypic rescue was achieved via suppression of AKT activity, a central regulator of mTORC1, MYC, and DC hepatocyte-driven hyperplasia. Thus, isogenic, iPS-derived admixed hepatostellate organoids offer insight into the liver pathologies in telomeropathies and provide a framework for evaluating emerging therapies.
2023-05-06 | GSE174018 | GEO
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
Project description:PARN deficiency is linked to the inherited disease Dyskeratosis Congenita and Familial Pulmonary Fibrosis. The aim of this experiment is to identify miRNAs that are regulated by PARN in human cells, deficiency of which could explain the disease phenotype in patients.
2018-12-29 | E-MTAB-7547 | biostudies-arrayexpress
Project description:Dyskeratosis congenita is a bone marrow failure syndrome characterized by the presence of short telomeres at presentation. The X-linked form is caused by mutations in the gene DKC1, encoding the protein dyskerin. Dyskerin is required for in the assembly and stability of telomerase and is also involved in ribosomal RNA (rRNA) processing where it converts specific uridines to pseudouridine. DC is thought to result from failure to maintain tissues, like blood, that are renewed by stem cell activity, suggesting induced pluripotent stem (iPS) cells from X-linked DC patients may provide information about the mechanisms involved. Here we show that in iPS cells with DKC1 mutations Q31E, A353V and ΔL37 telomere maintenance is compromised with short telomere lengths and decreased telomerase activity. The degree to which telomere lengths are affected by expression of telomerase during reprograming, or with ectopic expression of wild type dyskerin varies, with recurrent mutation A353V showing the most severe effect on telomere maintenance. A353V cells but not Q31E or ΔL37 cells, are refractory to correction by incorporation of a single copy of a wild type DKC1 cDNA into the AAVS1 safe harbor locus. None of the mutant cells show decreased pseudouridine levels in rRNA or defective rRNA processing. Finally transcriptome analysis of the iPS cells shows that WNT signaling is significantly decreased in all mutant cells, raising the possibility that defective WNT signaling may contribute to disease pathogenesis.
2015-03-13 | GSE66849 | GEO
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.
2015-09-08 | GSE71709 | GEO
Project description:The evolving genetic landscape of dyskeratosis congenita (DC) and DC-like (DCL) disorders
| PRJNA1026113 | ENA
Project description:Dyskerin is a pseudouridine synthase involved in fundamental cellular processes (including rRNA and snRNA modification and telomere stabilization), whose function is altered in X-linked dyskeratosis congenita and cancer. Dyskerin role in ribosome processing was suggested to underlie the alterations in mRNA translation described in cells lacking dyskerin function. We compared the protein contents of 5 replicates of ribosomal preparations from control or dyskerin-depleted human cells.
2015-05-07 | PXD001274 | Pride
Project description:Dyskeratosis congenita (DC) is an inherited multi-system disorder, characterized by oral leukoplakia, nail dystrophy, and abnormal skin pigmentation, as well as high rates of bone marrow failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the bone marrow stromal cell population (BMSCs, also known as bone marrow-derived mesenchymal stem cells), may contribute to the hematological phenotype.
2015-05-11 | GSE64789 | GEO
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
Project description:Dyskeratosis congenita (DC) is a complex inherited bone marrow failure syndrome which is principally a disorder of telomere maintenance. To date approximately 35% of cases remain uncharacterised at the genetic level. Whole exome sequencing on a large collection of uncharacterized DC and DC-like (DCL) families (n=167) has revealed several novel pathogenic variants within known susceptibility loci, POT1 and ZCCHC8, as well as the novel locus POLA1. Functional characterisation of identified POLA1 and POT1 pathogenic variants, uncovered their effect on protein-protein interactions that have critical implications for telomere maintenance. ZCCHC8 variants disrupt protein interactions that affect nuclear exosome targeting (NEXT) complex stoichiometry and its binding with the human silencing hub (HUSH) complex chromatin modifier MPP8. Global transcriptomic analysis revealed signatures of pervasive transcription that include several short (snRNA and snoRD) and long non-coding RNA (transposable elements; LINE-1) driving inflammation in ZCCHC8 patient blood cells. In summary, our studies inform the current genetic architecture of DC and DCL disorders, by revealing novel gene loci such as POLA1 and extend our current knowledge on disease mechanisms beyond the regulation of long non-coding RNA TERC.
2024-07-10 | GSE244915 | GEO