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Comprehensive DNA Methylation Analysis Using a Methyl-CpG-binding Domain Capture-based Method in Chronic Lymphocytic Leukemia Patients
Published on: June 16, 2017
Dynamic alterations of the transcriptome-wide m6A methylome in cytogenetically normal acute myeloid leukaemia during
Jinjing Zhang1, Tong Liu1, Yue Wang1
1Department of Hematology, the First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
Abstract:
Accumulating studies have indicated that N6-methyladenosine (m6A) plays an important role in acute myeloid leukaemia (AML). However, little is known about the m6A methylome at a transcriptome-wide scale in AML patients. We obtained three pairs of bone marrow (BM) samples from cytogenetically normal AML patients at the timepoints of diagnosis (AML) and relapse (R_AML) and three BM samples from healthy donors used as normal controls (NCs). Methylated RNA immunoprecipitation next-generation sequencing (MeRIP-Seq) was conducted to identify differences in the m6A methylomes between AML and NC and between R_AML and AML. We identified a total of 11,076 and 11,962 differential m6A peaks in AML and R_AML group, respectively. These dysregulated m6A peaks were detected on all chromosomes, especially chr1, chr19 and chr17, and were mainly enriched in 3' untranslated regions, stop codon and coding sequence regions. Moreover, GO and KEGG analyses indicated that m6A -modified genes were significantly enriched in cancer-related biological functions and pathways. Additionally, we identified a link between the m6A methylome and RNA transcriptome via combined analyses of MeRIP-seq and RNA-seq data. In addition, 5 genes, HSPG2, HOMER3, TSPO2, CXCL12 and FUT1 regulated by m6A modification potentially, were shown to be related to the prognosis of AML patients. Additionally, we detected the mRNA expression of major m6A regulators and potential target mRNA on the leukemogenesis and found that the expression of IGF2BP2, HSPG2 and HOMER3 were upregulated in AML at the time of diagnosis. Moreover, their expression became downregulated after remission and then elevated again at relapse. Our study provides the first data on the differential m6A methylome in AML patients during initial diagnosis and relapse. This study demonstrates a novel relationship between m6A modification and AML relapse and paves the way for further studies aimed at elucidating the epigenic mechanisms involved in the relapse of AML.
Insights
N6-methyladenosine (m6A) modification is altered in acute myeloid leukaemia (AML), particularly during relapse. This study reveals widespread m6A changes and identifies key genes linked to AML progression and prognosis.
Area of Science:
- Epigenetics
- Molecular Biology
- Oncology
Background:
- N6-methyladenosine (m6A) is a crucial epitranscriptomic modification implicated in acute myeloid leukaemia (AML).
- The comprehensive m6A methylome landscape in AML patients, especially during disease progression from diagnosis to relapse, remains largely unexplored.
Purpose of the Study:
- To investigate genome-wide m6A methylome alterations in AML patients at diagnosis and relapse compared to healthy controls.
- To identify m6A-modified genes and pathways associated with AML pathogenesis and relapse.
- To explore the relationship between m6A modifications, gene expression, and clinical outcomes in AML.
Main Methods:
- MeRIP-Seq was employed to profile the m6A methylome in bone marrow samples from AML patients (diagnosis and relapse) and healthy donors.
- Bioinformatic analyses, including differential peak analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, were performed.
- Integrated analysis of MeRIP-Seq and RNA-Seq data was conducted to link m6A modifications with gene expression patterns.
Main Results:
- Significant differential m6A peaks were identified in AML patients at diagnosis (11,076 peaks) and relapse (11,962 peaks) compared to controls.
- Dysregulated m6A peaks were enriched in 3' UTRs, stop codons, and coding sequences, particularly on chromosomes 1, 19, and 17.
- m6A-modified genes were significantly associated with cancer-related biological functions and pathways, and 5 genes (HSPG2, HOMER3, TSPO2, CXCL12, FUT1) were linked to AML prognosis.
- Upregulation of IGF2BP2, HSPG2, and HOMER3 was observed in AML at diagnosis, with dynamic changes during remission and relapse, suggesting their role in leukemogenesis.
Conclusions:
- This study presents the first comprehensive analysis of the differential m6A methylome in AML patients during diagnosis and relapse.
- m6A modification plays a significant role in AML relapse, offering new insights into the epigenetic mechanisms driving disease progression.
- The findings highlight potential therapeutic targets and diagnostic biomarkers for AML, particularly concerning relapse and treatment resistance.
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