Abstract
BackgroundLong noncoding enhancer RNAs (lnc-eRNAs) are a subset of stable eRNAs identified from annotated lncRNAs. They might act as enhancer activity-related therapeutic targets in cancer. However, the underlying mechanism of epigenetic activation and their function in cancer initiation and progression remain largely unknown.ResultsWe identify a set of lncRNAs as lnc-eRNAs according to the epigenetic signatures of enhancers. We show that these lnc-eRNAs are broadly activated in MLL-rearranged leukemia (MLL leukemia), an aggressive leukemia caused by a chromosomal translocation, through a mechanism by which the HOXA cluster initiates enhancer activity, and the epigenetic reader BRD4 cooperates with the coregulator MLL fusion oncoprotein to induce transcriptional activation. To demonstrate the functional roles of lnc-eRNAs, two newly identified lnc-eRNAs transcribed from the SEELA eRNA cluster (SEELA), SEELA1 and SEELA2, are chosen for further studies. The results show that SEELA mediated cis-activated transcription of the nearby oncogene Serine incorporate 2 (SERINC2) by directly binding to the K31 amino acid (aa) of histone H4. Chromatin-bound SEELA strengthens the interaction between chromatin and histone modifiers to promote histone recognition and oncogene transcription. Further studies show that the SEELA-SERINC2 axis regulated aspects of cancer metabolism, such as sphingolipid synthesis, to affect leukemia progression.ConclusionsThis study shows that lnc-eRNAs are epigenetically activated by cancer-initiating oncoproteins and uncovers a cis-activating mechanism of oncogene transcription control based on lnc-eRNA-mediated epigenetic regulation of enhancer activity, providing insights into the critical roles of lnc-eRNAs in cancer initiation and progression.
Highlights
Long noncoding enhancer RNAs are a subset of stable eRNAs identified from annotated lncRNAs
We identified a set of lncRNAs acting as lnc-eRNAs that are activated in Mixed Lineage Leukemia (MLL) leukemia through a HOXA initiation-BRD4 transcriptional activation mechanism, by which the MLL fusion downstream HOXA cluster initiates enhancer establishment, and the epigenetic reader BRD4 cooperates with the coregulator MLL fusion oncoprotein to induce enhancer transcription
We further showed that the newly identified lnc-eRNA, SEELA, directly interacted histone H4 to localize on chromatin and strengthened the binding between the histone modifier and chromatin to promote histone recognition and enhancer activity
Summary
Long noncoding enhancer RNAs (lnc-eRNAs) are a subset of stable eRNAs identified from annotated lncRNAs. The underlying mechanism of epigenetic activation and their function in cancer initiation and progression remain largely unknown. The genomic loci of lnc-eRNAs overlap with those of tissue-specific enhancers [6], and lnc-eRNA expression is tightly correlated with the epigenetic signatures of enhancers that are controlled by histone modifiers [7]. Dysregulation of enhancer activity, including abnormal expression of eRNAs, is frequently observed in cancer [8, 9], and targeting enhancer activity-related histone modifiers has shown promise in cancer treatment [10]. Extensive genome-wide studies have revealed that lncRNAs are dysregulated in almost all types of cancer [11, 12]; whether these lncRNAs act as lnc-eRNAs to regulate cancer initiation and progression remains largely unknown
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