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GEO help: Mouse over screen elements for information. |
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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.[RNA-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression 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 PG |
| Citation(s) |
37031307 |
| BioProject |
PRJNA879971 |
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| Submission date |
Sep 19, 2022 |
| Last update date |
Apr 12, 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) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (17)
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| GSM6592023 |
RNA-Seq of AML patient (AML2), relapse phase, replicate 1 |
| GSM6592024 |
RNA-Seq of AML patient (AML2), onset phase, replicate 1 |
| GSM6592025 |
RNA-Seq of AML patient (UD10), relapse phase, replicate 1 |
| GSM6592026 |
RNA-Seq of AML patient (UD10), onset phase, replicate 1 |
| GSM6592027 |
RNA-Seq of AML patient (UD5), relapse phase, replicate 1 |
| GSM6592028 |
RNA-Seq of AML patient (UD5), onset phase, replicate 1 |
| GSM6592029 |
RNA-Seq of AML patient (AML2), relapse phase, replicate 2 |
| GSM6592030 |
RNA-Seq of AML patient (AML2), onset phase, replicate 2 |
| GSM6592031 |
RNA-Seq of AML patient (UD10), relapse phase, replicate 2 |
| GSM6592032 |
RNA-Seq of AML patient (UD10), onset phase, replicate 2 |
| GSM6592033 |
RNA-Seq of AML patient (UD5), relapse phase, replicate 2 |
| GSM6592034 |
RNA-Seq of AML patient (UD5), onset phase, replicate 2 |
| GSM6592035 |
RNA-Seq of AML patient (AML2), relapse phase, replicate 3 |
| GSM6592036 |
RNA-Seq of AML patient (AML2), onset phase, replicate 3 |
| GSM6592037 |
RNA-Seq of AML patient (UD10), relapse phase, replicate 3 |
| GSM6592038 |
RNA-Seq of AML patient (UD10), onset phase, replicate 3 |
| GSM6592039 |
RNA-Seq of AML patient (UD5), relapse phase, replicate 3 |
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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 |
| GSE213684_normalized_counts.xlsx |
2.3 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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