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DNA Methylation in PRDM8 is a Biomarker for Dyskeratosis Congenita

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE75310 | GEO | 2016/05/23

SECONDARY ACCESSION(S): PRJNA303165

REPOSITORIES: GEO

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Project description:Aging is the consequence of intra- and extracellular events that promote cellular senescence. Dyskeratosis congenita (DC) is an example of a premature aging disorder caused by underlying telomere/telomerase-related mutations. Cells from these patients offer an opportunity to study telomere-related aging and senescence. Our previous work has found that telomere shortening stimulates DNA damage responses (DDR) and increases reactive oxygen species (ROS), thereby promoting entry into senescence. This work also found that telomere elongation via TERT expression, the catalytic component of the telomere-elongating enzyme telomerase, or p53 shRNA could decrease ROS by disrupting this telomere-DDR-ROS pathway. To further characterize this pathway, we performed a CRISPR/Cas9 knockout screen to identify genes that extend lifespan in DC cells. Of the cellular clones isolated due to increased lifespan, 34% had a guide RNA (gRNA) targeting CEBPB while gRNAs targeting WSB1, MED28 and p73 were observed multiple times. CEBPB is a transcription factor associated with activation of proinflammatory response genes suggesting that inflammation may be present in DC cells. The inflammatory response was investigated using RNA-Seq to compare DC and control cells. Expression of inflammatory genes were found to be significantly elevated (p<0.0001) in addition to a key subset of these inflammation-related genes (IL1B, IL6, IL8, IL12A, CXCL1 (GROa), CXCL2 (GROb), and CXCL5) which are regulated by CEBPB. Exogenous TERT expression led to downregulation of RNA/protein CEBPB expression and the inflammatory response genes suggesting a telomere-length dependent mechanism to regulate CEBPB. Furthermore, unlike exogenous TERT and p53 shRNA, CEBPB shRNA did not significantly decrease ROS suggesting that CEBPB’s contribution in DC cells’ senescence is ROS-independent. Our findings demonstrate a key role for CEBPB in engaging senescence by mobilizing an inflammatory response within DC cells.

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DNA Methylation in PRDM8 is a Biomarker for Dyskeratosis Congenita

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