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Profiling the epigenetic interplay of lncRNA RUNXOR and oncogenic RUNX1 in breast cancer cells by gene in situ cis-activation.


ABSTRACT: RUNX1 is frequently mutated as chromosomal translocations in a variety of hematological malignancies. Recent studies show that RUNX1 is also mutated somatically in many solid tumors. We have recently identified a 260 kb un-spliced intragenic overlapping long noncoding RNA RUNXOR in the RUNX1 locus, yet its role as an epigenetic regulator in tumors remains to be characterized. To delineate this RUNXOR-RUNX1 regulatory interplay in breast cancer cells, we devised a novel "gene in situ cis-activation" approach to activate the endogenous RUNXOR gene. We found that the in situ activation of RUNXOR lncRNA upregulated RUNX1 in cis from the P1 promoter. The preferred activation of the P1 promoter caused a shift to the RUNX1c isoform expression. Using a chromatin conformation capture (3C) approach, we showed that RUNXOR lncRNA epigenetically activated the RUNX1 P1 promoter in cis by altering the local chromatin structure. The binding of RUNXOR lncRNA triggered DNA demethylation and induced active histone modification markers in the P1 CpG island. Changes in RUNX1 isoform composition correlated with a trend to cell cycle arrest at G0/G1, although cell proliferation rate, apoptosis, and migration ability were not significantly changed. Our results reveal an underlying epigenetic mechanism by which the lncRNA regulates in cis the RUNX1 promoter usage in breast cancer cells, thereby shedding light on potential genetic therapies in malignancies in which RUNX1 loss-of-function mutations frequently occur.

PROVIDER: S-EPMC6726995 | BioStudies |

REPOSITORIES: biostudies

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