Long noncoding RNA FAM157C contributes to clonal proliferation in paroxysmal nocturnal hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease of hematopoietic stem cells (HSCs). Long noncoding RNAs (lncRNAs) perform a wide range of biological functions, including the regulation of gene expression, cell differentiation, and proliferation, but their role in PNH remains unclear.CD59− and CD59+ granulocytes and monocytes from 35 PNH patients were sorted. High-throughput sequencing was analyzed in 5 PNH patients, and differentially expressed lncRNAs and mRNAs were identified. The mRNAs with fragments per kilobase of exon model per million mapped fragments (FPKM) > 10 in at least 3 patients were selected, and experiments were performed to identify their upstream regulatory lncRNAs. The expression of selected mRNAs and lncRNAs was verified by qRT‒PCR, and the correlation of these expression patterns with clinical data from other 30 PNH patients was analyzed. Then, the functions of the lncRNAs were studied in the PIGA-KO-THP-1 cell line.Transcription analysis revealed 742 upregulated and 1376 downregulated lncRNAs and 3276 upregulated and 213 downregulated mRNAs. After deep screening, 8 highly expressed mRNAs that were related to the NF-κB pathway were analyzed to determine coexpression patterns. LINC01002, FAM157C, CTD-2530H12.2, XLOC-064331 and XLOC-106677 were correlated with the 8 mRNAs. After measuring the expression of these molecules in 30 PNH patients by qRT‒PCR, lncRNA FAM157C was verified to be upregulated in the PNH clone, and its expression levels were positively correlated with the LDH levels and CD59− granulated and monocyte cell ratios. After knockdown of the FAM157C gene in the PIGA-KO-THP-1 cell line, we found that the cells were arrested in the G0/G1 phase and S phase, the apoptosis rate increased, and the cell proliferation decreased.LncRNA FAM157C was proven to promote PNH clone proliferation, and this is the first study to explore the role of lncRNAs in PNH.

The histone demethylase JMJD1C regulates CPS1 expression and promotes the proliferation of paroxysmal nocturnal haemoglobinuria clones through cell metabolic reprogramming

“…As previous studies have shown that epigenetic modification plays an important role in the proliferation of PNH clones and regulates CPS1 expression in a variety of diseases, we speculated that epigenetic modification may also be involved in the abnormal expression of CPS1 in PNH. Therefore, we reviewed the differentially expressed genes (DEGs) (|log 2 FC| ≥ 5, p .adj < 0.05) identified from CD59 − and CD59 + cell RNA‐sequencing data of PNH patients 20 . We selected the Kyoto Encyclopedia of Genes and Genomes (KEGG) BRITE database chromosome and related protein (BR:hsa03036)‐histone modified protein pathway; five genes were selected, among which JMJD1C (log 2 FC = 5.179, p .adj = 0.0381), JMJD6 (log 2 FC = Inf, p .adj = 0.00013) and KDM5C (log 2 FC = Inf, p .adj = 0.0343) were associated with histone methylation, and NCOA1 (log 2 FC = Inf, p .adj = 0.000014) and NCOA3 (log 2 FC = Inf, p .adj = 0.0401) were associated with histone acetylation.…”

Genetic determinants of blood gene expression and splicing and their contribution to molecular phenotypes and health outcomes

“…This included 543 cis -sGenes that were not identified as cis -eGenes. The long non-coding RNA FAM157C , which is involved in cell proliferation and induction of apoptosis, 21 contained the most splicing events (n=128, within 11 clusters defined by shared splice donor or acceptor sites). While this gene is known to contain 33 exons, the splicing events were mostly intronic (n=105/128) and rarely overlapping previously defined exon boundaries (n=9/128).…”