Abstract
Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by genetic and epigenetic aberrations that alter the differentiation capacity of myeloid progenitor cells. The transcription factor CEBPα is frequently mutated in AML patients leading to an increase in DNA methylation in many genomic locations. Previously, it has been shown that ecCEBPα (extra coding CEBP α) - a lncRNA transcribed in the same direction as CEBPα gene - regulates DNA methylation of CEBPα promoter in cis. Here, we hypothesize that ecCEBPα could participate in the regulation of DNA methylation in trans. Method: First, we retrieved the methylation profile of AML patients with mutated CEBPα locus from The Cancer Genome Atlas (TCGA). We then predicted the ecCEBPα secondary structure in order to check the potential of ecCEBPα to form triplexes around CpG loci and checked if triplex formation influenced CpG methylation, genome-wide. Results: Using DNA methylation profiles of AML patients with a mutated CEBPα locus, we show that ecCEBPα could interact with DNA by forming DNA:RNA triple helices and protect regions near its binding sites from global DNA methylation. Further analysis revealed that triplex-forming oligonucleotides in ecCEBPα are structurally unpaired supporting the DNA-binding potential of these regions. ecCEBPα triplexes supported with the RNA-chromatin co-localization data are located in the promoters of leukemia-linked transcriptional factors such as MLF2. Discussion: Overall, these results suggest a novel regulatory mechanism for ecCEBPα as a genome-wide epigenetic modulator through triple-helix formation which may provide a foundation for sequence-specific engineering of RNA for regulating methylation of specific genes.
Highlights
Acute myeloid leukemia (AML) is a malignant tumor characterized by the proliferation of undifferentiated myeloblasts[1,2]
Results ecCEBPα forms triplexes with promoter regions and affects promoter methylation The current study explores the potential of the long non-coding RNAs (lncRNA) ecCEBPα in the modulation of global CpG methylation status in trans via direct interaction with DNA regions. ecCEBPα, reported in work by Di Russio et al.[20], is located on chromosome 19 and transcribed from the CEBPα locus (Figure 1a)
We observed that regions capable of forming triplexes with ecCEBPα remain protected from global DNA hypermethylation observed in case of a mutation in a CEBPα locus (Figure 1c, Fisher’s exact test, p-value
Summary
Acute myeloid leukemia (AML) is a malignant tumor characterized by the proliferation of undifferentiated myeloblasts[1,2]. Cases of AML with chromosomal rearrangements as t(15;17) [PML-RARA], t(9;22) [BCR-ABL], inv(16) [CBFB-MYH11], t(8;21) [RUNX1-ETO] are called cytogenetically abnormal (CA-AML), while cases with genetic abnormalities (including frequent mutations in DNMT3A, NPM1, CEBPα, IDH1/2, TET2, FLT3-ITD) are called cytogenetically normal (CN-AML)[1,4]. The former accounts for 50–55%, while the latter accounts for 45–50% of diagnosed AML cases[6,7]. Results: Using DNA methylation profiles of AML patients with a mutated CEBPα locus, we show that ecCEBPα could interact with DNA by forming DNA:RNA triple helices and protect regions near its binding sites from global DNA methylation. Discussion: Overall, these results suggest a novel regulatory mechanism for ecCEBPα as a genome-wide epigenetic modulator through triple-helix formation which may provide a foundation for sequence-specific engineering of RNA for regulating methylation of specific genes
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