Modulation of specific cell cycle phases in human embryonic stem cells by lncRNA RNA decoys

Abstract

Recent studies have shown that long noncoding RNAs (lncRNAs) are crucial regulators of human embryonic stem cells (hESCs). However, modes of actions of lncRNAs in hESCs are not well illustrated. Here, we predicted a regulatory network in hESCs in which lncRNAs interact with TFs and thereby control the expressions of downstream targets of TFs. The predicted network is comprised of 2289 3-motif subgraphs which are characterized by 3 nodes: (i) a lncRNA which is predicted to interact with (ii) a TF and (iii) a gene which is a target of TF and coexpressing with lncRNA. We performed functional annotation of the network by identifying hub nodes followed by pathway enrichment study, which unveiled an active G1-S cell cycle phase transition-specific subnetwork that encompasses 2 lncRNAs, MALAT1 and DANCR. Our analysis revealed that MALAT1 and DANCR might be playing key roles in G1-S phase transition by acting as RNA decoy via interacting with crucial stemness maintaining TFs. We predicted that MALAT1 possibly compete with DNMT1 and CDCA7 genes to bind to E2F1 thereby interrupting repression of DNMT1 and activation of CDCA7 by E2F1 in hESCs, whereas DANCR possibly competes with IPO7 gene to bind to MYC thereby interrupting MYC-mediated activation of IPO7 in hESCs. Both of these are conjectured to contribute to rapid G1-S phase transition aiding in stemness maintenance of hESCs. This study presents a crucial TF target cross talks mediated by lncRNAs in hESCs regulating its properties which needs further investigation.

The Role of the lncRNA MALAT1 in Neuroprotection against Hypoxic/Ischemic Injury

“…In addition to regulating alternative splicing, MALAT1 can also regulate gene transcription and epigenetic modification. MALAT1 may compete with DNA methyltransferase (DNMT) 1 and cell division cycle associated 7 (CDCA7) to bind to the E2F1 transcription factor, thereby interrupting inhibition of DNMT1 and the activation of CDCA7 by E2F1 [ 26 ]. In many cases, hypoxia/ischemia can cause DNA promoter methylation of certain genes, thereby inhibiting the expression of the gene and causing damage [ 27 , 28 ].…”

“…In many cases, hypoxia/ischemia can cause DNA promoter methylation of certain genes, thereby inhibiting the expression of the gene and causing damage [ 27 , 28 ]. It could be predicted that MALAT1 may combine with DNMT to reduce the methylation of certain gene promoters under hypoxic conditions and promote their expression, resulting in nerve cell protection [ 26 ]. Therefore, MALAT1 may have a protective effect on nerve cells through epigenetics.…”

Network characterization linc1393 in the maintenance of pluripotency provides the principles for lncRNA targets prediction

“…Presently, lncRNAs are known to play diverse functional roles in various biological pathways, including disease progression and developmental regulation, and are particularly true in embryonic stem cells (ESCs), where subtle changes in lncRNA expression can lead to the loss of pluripotency. 4 , 10 , 17 , 18 , 19 , 20 , 21 , 22 , 23 For example, lncRNA Panct1 can maintain mouse ESC (mESC) identity by regulating TOBF1 recruitment to Oct-Sox motifs in the early G1 phase. 24 However, the functional mechanisms through which many lncRNAs contribute to pluripotency have not yet been fully explored.…”

Effect of m6A methyltransferase METTL3 ‐mediated MALAT1/E2F1/AGR2 axis on adriamycin resistance in breast cancer

“…[ 12 ] It was found that MALAT1 may play a key role in G1‐S phase transition by interacting with key stem cell maintenance transcription factors (TFs), including E2F1 by acting as RNA decay in human embryonic stem cells. [ 13 ] And E2F1 was found to promote anterior gradient 2 (AGR2) transcription, a protein belonging to the protein disulfide isomerase (PDI) family, which is highly expressed in multiple cancers and promotes angiogenesis to modulate cancer progression. [ 14 ] In the present study, we aimed to delineate the mechanisms of m6A methyltransferase METTL3 mediated MALAT1/E2F1/AGR2 axis on adriamycin resistance in breast cancer.…”