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Status |
Public on Apr 12, 2023 |
Title |
High-resolution Nanopore methylome-maps reveal random hyper-methylation at CpG-poor regions as driver of chemoresistance in leukemias. [methylation] |
Organism |
Homo sapiens |
Experiment type |
Methylation profiling by high throughput sequencing
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Summary |
Aberrant DNA-methylation at CpG dinucleotides is a hallmark of cancer and is associated with the emergence of resistance to anti-cancer treatment, though molecular mechanisms and biological signifi- cance remain elusive. Genome-scale methylation maps by currently used methods are based on chemical modification of DNA and are best suited for analyses of methylation at CpG-rich regions (CpG islands). We report the first high-coverage whole-genome map in cancer using the long-read nanopore technol- ogy, which allows simultaneous DNA-sequence and -methylation analyses on native DNA. We analyzed clonal epigenomic/genomic evolution in Acute Myeloid Leukemias (AMLs) at diagnosis and relapse, af- ter chemotherapy. Long-read sequencing coupled to a novel computational method allowed definition of differential methylation at unprecedented resolution (> 99% CpGs), extending analyses of CpG is- lands to sparse CpGs, which represent half of all differentially-methylated regions. We showed that the
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Overall design |
relapse methylome is characterized by hypermethylation at both CpG islands and sparse CpGs. Hyper- methylated genes, however, only accounted for < 5% of all differentially-expressed genes (DEGs) in the relapsed AMLs and were not enriched for chemoresistance genes. A few under-expressed transcription- factors (1 to 6 in the different AMLs) hyper-methylated at sparse CpGs support ∼ 40% DEGs and are highly-enriched in chemoresistance genes. Hypermethylated regions at sparse CpGs were poorly con- served in the relapsed AMLs, under-represented at their genomic positions and showed high methylation- entropy, as compared to CpG islands. Relapsed AMLs carried a few patient-specific structural-variants and DNA-mutations, apparently not involved in drug-resistance. Thus, drug-resistance in AMLs is due to the selection of random epigenetic alterations at sparse CpGs of a few transcription factors, which then induce reprogramming of the relapsing phenotype, independently of clonal genomic-evolution.
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Contributor(s) |
Magi A, Mattei G, Mingrino A, Caprioli C, Ronchini C, Frig`e G, Semeraro R, Bolognini D, Rambaldi A, Candoni A, Colombo E, Mazzarella L, Pelicci P |
Citation(s) |
37031307 |
BioProject |
PRJNA879930 |
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Submission date |
Sep 19, 2022 |
Last update date |
Apr 13, 2023 |
Contact name |
Gianluca Mattei |
E-mail(s) |
gianluca.mattei@unifi.it
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Organization name |
Università degli Studi di Firenze
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Street address |
Via di S. Marta, 3
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City |
Firenze |
State/province |
FI |
ZIP/Postal code |
50139 |
Country |
Italy |
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Platforms (1) |
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Samples (6)
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GSM6592040 |
AML patient (AML2), methylation table, relapse phase |
GSM6592041 |
AML patient (AML2), methylation table, onset phase |
GSM6592042 |
AML patient (UD5), methylation table, relapse phase |
GSM6592043 |
AML patient (UD5), methylation table, onset phase |
GSM6592044 |
AML patient (UD10), methylation table, relapse phase |
GSM6592045 |
AML patient (UD10), methylation table, onset phase |
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This SubSeries is part of SuperSeries: |
GSE213686 |
High-resolution Nanopore methylome-maps reveal random hyper-methylation at CpG-poor regions as driver of chemoresistance in leukemias. |
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Supplementary file |
Size |
Download |
File type/resource |
GSE213685_RAW.tar |
1019.8 Mb |
(http)(custom) |
TAR (of TSV) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
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