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Series GSE213684 Query DataSets for GSE213684
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
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
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.
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
Submission date Sep 19, 2022
Last update date Apr 12, 2023
Contact name Gianluca Mattei
Organization name Università degli Studi di Firenze
Street address Via di S. Marta, 3
City Firenze
State/province FI
ZIP/Postal code 50139
Country Italy
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (17)
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
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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GSE213684_normalized_counts.xlsx 2.3 Mb (ftp)(http) XLSX
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