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Background  Long 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.    Results  We 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.    Conclusions  This 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.    Supplementary information   Supplementary information  accompanies this paper at 10.1186/s13059-020-02186-x.

Cis-acting lnc-eRNA SEELA directly binds histone H4 to promote histone recognition and leukemia progression