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

Genome Biology

Wei Huang¹  Ke Fang¹  Tian-Qi Chen¹  Yue-Qin Chen¹  Zhan-Cheng Zeng¹  Yu-Meng Sun¹  Wen-Tao Wang¹  Cai Han¹  Qian-Qian Yang¹  Qi Pan¹  Lin-Yu Sun¹  Xue-Qun Luo² 

[1] MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, 510275, Guangzhou, China;The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, China;

关键词: Lnc-eRNA;    SEELA;    Histone H4;    Histone recognition;    Enhancer activity;    Sphingolipid metabolism;    MLL;   

DOI  :  10.1186/s13059-020-02186-x

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY