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Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita (HITS-CLIP)

ABSTRACT: Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita (HITS-CLIP)

PROVIDER: PRJNA559865 | ENA |

REPOSITORIES: ENA

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	SRR9952784.fastq.gz	Fastqsanger.gz

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Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita (HITS-CLIP)

Project description:We identify nucleophosmin (NPM1) as an essential regulator of 2’-O-methylation on rRNA by directly binding C/D box small nucleolar RNAs (snoRNAs), thereby modulating translation. We demonstrate the importance of 2’-O-Me regulated translation for cellular growth, differentiation and hematopoietic stem cells (HSC) maintenance, and show that Npm1-inactivation in adult HSCs results in bone marrow failure (BMF). We identify NPM1 germline mutations in DC patients presenting with BMF; and demonstrate that they are deficient in snoRNA binding. CRISPR knock-in mice harboring the DC germline NPM1 mutation recapitulate both hematological and non-hematological features of DC. Thus, our findings provide a direct demonstration of the role of 2’-O-Me in the pathogenesis of human disease

2019-08-13 | GSE135724 | GEO

Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita

Project description:Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita

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Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita (microarray)

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Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita (microarray)

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Germline NPM1 mutations lead to altered rRNA 2'-O-methylation and cause dyskeratosis congenita.

Project description:RNA modifications are emerging as key determinants of gene expression. However, compelling genetic demonstrations of their relevance to human disease are lacking. Here, we link ribosomal RNA 2'-O-methylation (2'-O-Me) to the etiology of dyskeratosis congenita. We identify nucleophosmin (NPM1) as an essential regulator of 2'-O-Me on rRNA by directly binding C/D box small nucleolar RNAs, thereby modulating translation. We demonstrate the importance of 2'-O-Me-regulated translation for cellular growth, differentiation and hematopoietic stem cell maintenance, and show that Npm1 inactivation in adult hematopoietic stem cells results in bone marrow failure. We identify NPM1 germline mutations in patients with dyskeratosis congenita presenting with bone marrow failure and demonstrate that they are deficient in small nucleolar RNA binding. Mice harboring a dyskeratosis congenita germline Npm1 mutation recapitulate both hematological and nonhematological features of dyskeratosis congenita. Thus, our findings indicate that impaired 2'-O-Me can be etiological to human disease.

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Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-08-13 | GSE135726 | GEO

DNA Methylation in PRDM8 is a Biomarker for Dyskeratosis Congenita

Project description:Dyskeratosis congenita (DKC) is characterized by impaired telomere maintenance and reveals clinical features of premature aging. So far, diagnosis of DKC relies particularly on telomere length screening raising the need for additional biomarkers. In this study, we analysed global DNA methylation (DNAm) profiles of DKC patients. Age-associated DNAm changes were not generally accelerated in DKC. However, we observed significant hypermethylation in the gene for PR domain containing 8 (PRDM8). Notably, the same genomic region revealed hypermethylation in aplastic anemia (AA), and Down syndrome (DS), indicating that there might be an association with premature aging syndromes. Site-specific analysis of DNAm level in PRDM8 with pyrosequencing and MassArray validated aberrant hypermethylation in 14 DKC patients and 27 AA patients. Notably, telomere length was not directly correlated with DNAm in PRDM8, indicating that the two methods are complementary. In conclusion, DNAm at PRDM8 provides a new biomarker to support diagnosis of of AA and DKC.

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The evolving genetic landscape of dyskeratosis congenita (DC) and DC-like (DCL) disorders

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.

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