Abstract
Long non-coding RNAs (lncRNAs) are emerging as important regulators of cellular processes and are extensively involved in the development of different cancers; including leukemias. As one of the accepted methods of lncRNA function is affecting chromatin structure; lncRNA binding has been shown for different chromatin modifiers. Histone lysine methyltransferases (HKMTs) are also subject of lncRNA regulation as demonstrated for example in the case of Polycomb Repressive Complex 2 (PRC2). Mixed Lineage Leukemia (MLL) proteins that catalyze the methylation of H3K4 have been implicated in several different cancers; yet many details of their regulation and targeting remain elusive. In this work we explored the RNA binding capability of two; so far uncharacterized regions of MLL4; with the aim of shedding light to the existence of possible regulatory lncRNA interactions of the protein. We demonstrated that both regions; one that contains a predicted RNA binding sequence and one that does not; are capable of binding to different RNA constructs in vitro. To our knowledge, these findings are the first to indicate that an MLL protein itself is capable of lncRNA binding.
Highlights
Long non-coding RNAs are transcribed RNA molecules longer than 200 nucleotides that do not code for translated proteins
These regions are found at various positions in the proteins and vary in length from a couple of amino acids to almost a hundred residues, suggesting that RNA binding might be a common feature in Mixed Lineage Leukemia (MLL) proteins
Our expectation was that the isolated small regions of the MLL4 protein would bind RNAs in a nonspecific manner, such as was observed for the isolated Polycomb Repressive Complex 2 (PRC2) complex components [34]
Summary
Long non-coding RNAs (lncRNAs) are transcribed RNA molecules longer than 200 nucleotides that do not code for translated proteins. The human genome is estimated to code for about 58,000 lncRNAs [1], that are being more and more recognized as central players in a plethora of biological processes They can act as flexible scaffolds providing binding platforms for different proteins, they can interfere with other endogenous RNAs acting as microRNA “sponges” and they can modify chromatin state [2], regulating the expression of various proteins. Functioning MLL3 and MLL4 act as tumor suppressors [23], mutations affecting their activity or stability can result in cancer development Despite their central role in several types of cancers, many open questions regarding the regulation of the activity and the targeting of the MLL complexes remain unanswered. Taken the analogy of the PRC2 complex, where more than one complex subunits are capable of lncRNA binding, we aimed at testing the ability of MLL4 to bind different RNA molecules
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