High methylation of the 4-aminobutyrate aminotransferase gene predicts a poor prognosis in patients with myelodysplastic syndrome

Zhao, Guangjie; Li, Nianyi; Li, Shuang; Wu, Wanling; Wang, Xiaoqin; Gu, Jingmin

doi:10.3892/ijo.2018.4652

Cited by 15 publications

(17 citation statements)

References 38 publications

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“…In addition to genetic alterations, epigenetic modifications, especially for DNA methylation were also reported to be participated in cancer progression including MDS [24][25][26] . Previous studies almost focused on the single gene change during MDS progression, such as CDKN2B, SOCS1, NR4A2, ABAT, ID4, GPX3, SOX30, and so on [9][10][11][27][28][29][30] . However, few studies demonstrated the whole-genome DNA methylation alterations during MDS progression.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes

Zhou

Zhang

et al. 2020

Cell Death Dis

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The potential mechanism of myelodysplastic syndromes (MDS) progressing to acute myeloid leukemia (AML) remains poorly elucidated. It has been proved that epigenetic alterations play crucial roles in the pathogenesis of cancer progression including MDS. However, fewer studies explored the whole-genome methylation alterations during MDS progression. Reduced representation bisulfite sequencing was conducted in four paired MDS/secondary AML (MDS/sAML) patients and intended to explore the underlying methylation-associated epigenetic drivers in MDS progression. In four paired MDS/sAML patients, cases at sAML stage exhibited significantly increased methylation level as compared with the matched MDS stage. A total of 1090 differentially methylated fragments (DMFs) (441 hypermethylated and 649 hypomethylated) were identified involving in MDS pathogenesis, whereas 103 DMFs (96 hypermethylated and 7 hypomethylated) were involved in MDS progression. Targeted bisulfite sequencing further identified that aberrant GFRA1, IRX1, NPY, and ZNF300 methylation were frequent events in an additional group of de novo MDS and AML patients, of which only ZNF300 methylation was associated with ZNF300 expression. Subsequently, ZNF300 hypermethylation in larger cohorts of de novo MDS and AML patients was confirmed by real-time quantitative methylation-specific PCR. It was illustrated that ZNF300 methylation could act as a potential biomarker for the diagnosis and prognosis in MDS and AML patients. Functional experiments demonstrated the anti-proliferative and pro-apoptotic role of ZNF300 overexpression in MDS-derived AML cell-line SKM-1. Collectively, genome-wide DNA hypermethylation were frequent events during MDS progression. Among these changes, ZNF300 methylation, a regulator of ZNF300 expression, acted as an epigenetic driver in MDS progression. These findings provided a theoretical basis for the usage of demethylation drugs in MDS patients against disease progression.

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Section: Discussionmentioning

confidence: 99%

Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes

Zhou

Zhang

et al. 2020

Cell Death Dis

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“…Our previous study identified a set of methylated genes (8). One of these genes, 4-aminobutyrate aminotransferase ( ABAT ), was highly methylated and its expression was reduced in MDS patients compared with that noted in healthy controls (8,9). The ABAT gene is localized on chromosome 16p13.2 and encodes a protein responsible for the catabolism of γ-aminobutyric acid ( GABA , an important neurotransmitter in the central nervous system) into succinic semialdehyde (10).…”

Section: Introductionmentioning

confidence: 99%

Role of 4‑aminobutyrate aminotransferase (ABAT) and the lncRNA co‑expression network in the development of myelodysplastic syndrome

Chen

Zhao

et al. 2019

Oncol Rep

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IncRNAs play an important role in the regulation of gene expression. The present study profiled differentially expressed lncRNAs (DELs) and mRNAs (DEMs) in myelodysplastic syndrome (MDS) to construct a 4-aminobutyrate aminotransferase (ABAT)-DEL-DEM co-expression network in MDS development using the Agilent human BeadChips and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and network analyses. Compared with controls, there were 543 DELs and 2,705 DEMs in MDS patients, among which 285 (52.5%) DELs were downregulated and 258 (47.5%) DELs were upregulated, whereas 1,521 (56.2%) DEMs were downregulated and 1,184 (43.70%) DEMs were upregulated in MDS patients. The ABAT-DEL-DEM co-expression network contained six DELs that were co-expressed with ABAT in MDS. The GO analysis revealed that the co-expression network mainly participated in response to organic cyclic compound, cell proliferation, cell part morphogenesis, regulation of cell proliferation and enzyme-linked receptor protein signaling pathways, while the KEGG database showed that the co-expression network was involved in various pathways, such as phagosome and metabolic pathways. Furthermore, the expression of a selected DEL (lncENST00000444102) and ABAT was shown to be significantly downregulated in MDS patients, and in SKM-1 and THP-1 cells. The selected lncENST00000444102 was then overexpressed and ABAT expression was knocked down in the MDS cell lines using lentiviral transfection. In addition, lncENST00000444102 overexpression reduced the viability and increased the apoptosis of MDS cells, ABAT expression was upregulated by lncENST00000444102.

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“…In addition to genetic alterations, epigenetic modi cations especially in DNA methylation have been shown involved in cancer progression including MDS [24][25][26]. Previous studies almost focused on the single gene change during MDS progression, such as CDKN2B, SOCS1, NR4A2, ABAT, ID4, GPX3, SOX30, and etc [9][10][11][27][28][29][30]. However, little studies showed the whole-genome DNA methylation alterations during MDS progression.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Methylation Sequencing Identifies Progression-Related Epigenetic Drivers in Myelodysplastic Syndromes

Zhou

Zhang²,

Xu³

et al. 2020

Preprint

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Background: The mechanism underlying disease progression of myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML) remains poorly elucidated. Epigenetic alterations are increasingly implicated in the pathogenesis of cancer progression including MDS. However, little studies explored the whole-genome methylation alterations during MDS progression.Methods: We conducted reduced representation bisulfite sequencing in four paired MDS/secondary AML (MDS/sAML) patients and intended to discover methylation-associated epigenetic drivers in MDS progression.Results: In four paired MDS/sAML patients, cases at sAML stage showed significantly increased methylation level when compared with their matched MDS stage. A total of 1090 differentially methylated fragments (DMFs) (441 hypermethylated and 649 hypomethylated) were identified involved in MDS pathogenesis, whereas 103 DMFs (96 hypermethylated and 7 hypomethylated) were identified involved in MDS progression. Further targeted bisulfite sequencing identified aberrant GFRA1, IRX1, NPY, and ZNF300 methylation was frequent events in additional de novo MDS and AML patients, of which only ZNF300 methylation was associated with ZNF300 expression. Moreover, ZNF300 hypermethylation in larger cohorts of de novo MDS and AML patients was further confirmed by real-time quantitative methylation-specific PCR. Clinical studies showed that ZNF300 methylation could act as a potential biomarker helpful for the diagnosis and prognosis in MDS and AML patients. In in vitro experiments, overexpression of ZNF300 exhibited anti-proliferative and pro-apoptotic effects in MDS-derived AML cell line SKM-1.Conclusions: Genome-wide DNA hypermethylation was a frequent event during MDS progression. Among these changes, ZNF300 methylation through the regulation of ZNF300 expression acted as an epigenetic driver in MDS progression. These findings give a theoretical basis for investigating and using the efficacy of DNMT inhibitors in MDS patients against disease progression, and provide new insights for targeted therapy in MDS.

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High methylation of the 4-aminobutyrate aminotransferase gene predicts a poor prognosis in patients with myelodysplastic syndrome

Cited by 15 publications

References 38 publications

Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes

Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes

Role of 4‑aminobutyrate aminotransferase (ABAT) and the lncRNA co‑expression network in the development of myelodysplastic syndrome

Genome-Wide Methylation Sequencing Identifies Progression-Related Epigenetic Drivers in Myelodysplastic Syndromes

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