Abstract
BackgroundRUNX1 gene, a master regulator of the hematopoietic process, participates in pathological conditions as a partner for several genes in chromosomal translocations. One of the most frequent chromosomal translocations found in acute myeloid leukemia patients is the t(8;21), in which RUNX1 and ETO genes recombine. In RUNX1 gene, the DNA double-strand breaks that originate the t(8;21) are generated in the intron 5, specifically within three regions designated as BCR1, BCR2, and BCR3. To date, what determines that these regions are more susceptible to DNA double-strand breaks is not completely clear. In this report, we characterized RUNX1 intron 5, by analyzing DNase-seq and ChIP-seq data, available in the ENCODE Project server, to evaluate DNaseI hypersensitivity and the presence of the epigenetic mark H3K4me3 in 124 and 51 cell types, respectively.ResultsOur results show that intron 5 exhibits an epigenetic mark distribution similar to known promoter regions. Moreover, using the online tool YAPP and available CAGE data from the ENCODE Project server, we identified several putative transcription start sites within intron 5 in regions BCR2 and BCR3. Finally, available EST data was analyzed, identifying a novel uncharacterized long non-coding RNA, which is expressed in hematopoietic cell lines as shown by RT-PCR. Our data suggests that the core promoter of the novel long non-coding RNA locates within the region BCR3.ConclusionWe identified a novel long non-coding RNA within RUNX1 intron 5, transcribed from a promoter located in the region BCR3, one of the chromosomal breakpoints of RUNX1 gene.
Highlights
RUNX1 gene, a master regulator of the hematopoietic process, participates in pathological conditions as a partner for several genes in chromosomal translocations
As it has been previously described, RUNX1 intron 5 is involved in the generation of the chromosomal translocation (8;21) in Acute myeloid leukemia (AML) patients; we expected to find an indication of chromatin accessibility along the region involved in the translocation in myeloid cells
To further compare RUNX1 intron 5, we selected the well-known major-breakpoint cluster regions (BCRs) region from the BCR gene, again finding the DNaseI hypersensitivity presence that resembles an accessible region (Fig. 1c). This indicates that chromosomal breakpoints localize within accessible genomic regions and that chromatin accessibility is not restricted to the cell type in which the genomic aberration t(8;21) is expected to occur in pathological conditions
Summary
RUNX1 gene, a master regulator of the hematopoietic process, participates in pathological conditions as a partner for several genes in chromosomal translocations. One of the most frequent chromosomal translocations found in acute myeloid leukemia patients is the t(8;21), in which RUNX1 and ETO genes recombine. In RUNX1 gene, the DNA double-strand breaks that originate the t(8;21) are generated in the intron 5, within three regions designated as BCR1, BCR2, and BCR3. One of the most frequent reciprocal translocations, found in 4–8.3% of AML patients, is the t(8;21) [3]. In this translocation, the genes RUNX1 (AML1, CBFA2) and ETO (RUNX1T1, MTG8) recombine, generating a fusion protein that disrupts the hematopoietic process [4, 5]. RUNX1 gene is the master regulator of definitive hematopoiesis in humans [6, 7]; defective cell differentiation contributes to the onset of leukemia
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