SUZ12 participates in the proliferation of PNH clones by regulating histone H3K27me3 levels

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a disease involving hematopoietic stem cell membrane defects caused by acquired phosphatidylinositol glycan anchor biosynthesis class A (PIGA) mutations. In this study, 97 target genes were selected as a target gene panel and screened in 23 PNH patients via the sequencing of specific DNA target regions. Through functional analysis, we identified that suppressor-of-Zeste 12 (SUZ12) may be involved in the proliferation of PNH clones. mRNA and protein expression levels of SUZ12 and the trimethylation level of histone H3 at lysine 27 (H3K27) in CD59peripheral blood leukocytes from PNH patients were higher than those in CD59 + cells from PNH patients and peripheral blood leukocytes from healthy controls.In addition, the relative expression of SUZ12 in PNH patients was positively correlated with Ret% and the proportion of PNH clones. When we knocked down SUZ12 expression in a PIGA knockdown THP-1 cell line (THP-1 KD cells), the trimethylation of histone H3K27(H3K27me3) and cell proliferation decreased, apoptosis increased, and cell cycle arrest occurred in G0/G1 phase. In conclusion, SUZ12 participates in the proliferation of PNH clones by regulating histone H3K27me3 levels. Our results may provide new therapeutic targets and possibilities for PNH patients.

High exposure variance enables candidate biomarker detection in a small EWAS of methylmercury-exposed Peruvian adults

“…3-13 ). Signals of gene repression include repressive histone modifications (e.g., H3K27me3) and loss of methylation (indicating binding and activation) in regions associated with binding of proteins that deposit repressive histone modifications (e.g., polycomb repressive complex components EZH2 65 and SUZ12 66 ) or remove activating histone modifications (e.g., SMARCA4, a component of the SWI/SNF chromatin remodeling complex 67 , which recruits histone deacetylase repressor complexes 68 ).…”

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

“…Epigenetic modification is an important regulatory process 9 that is closely related to CPS1‐mediated metabolic reprogramming 25,26 . As our previous studies confirmed that histone modification plays an important role in the proliferation of PNH clones, 16 we hypothesize that abnormal CPS1 expression in PNH patients may be related to histone modification. Further experiments proved that the histone demethylase JMJD1C was upregulated in abnormal PNH clones, negatively correlated with CPS1 expression and positively correlated with the PNH clone proportion.…”

“…Abnormal CPS1 expression has been found in a variety of tumours, 11–14 in which CPS1 regulates cellular biological behaviours such as proliferation, apoptosis and migration by promoting the synthesis of its downstream product carbamoyl phosphate (CP) or by affecting cell metabolism 15 . Our previous studies revealed that the CPS1 expression level in the peripheral blood leucocytes of PNH patients is lower than that in the peripheral blood leucocytes of healthy controls (HCs) 16 . In this study, we further clarified the role of CPS1 in the proliferation of PNH clones and its mechanism, identified the histone demethylase JMJD1C as a regulator of CPS1 expression in PNH, and preliminarily explored the effect of histone demethylase inhibitors as potential treatment strategies for inhibiting the proliferation of PNH clones in PNH cells and a PNH mouse model.…”

“…15 Our previous studies revealed that the CPS1 expression level in the peripheral blood leucocytes of PNH patients is lower than that in the peripheral blood leucocytes of healthy controls (HCs). 16 In this study, we further clarified the role of CPS1 in the proliferation of PNH clones and its mechanism, identified the histone demethylase JMJD1C as a regulator of CPS1 expression in PNH, and preliminarily explored the effect of histone demethylase inhibitors as potential treatment strategies for inhibiting the proliferation of PNH clones in PNH cells and a PNH mouse model.…”