LncPRESS1 Is a p53-Regulated LncRNA that Safeguards Pluripotency by Disrupting SIRT6-Mediated De-acetylation of Histone H3K56

Abstract

SUMMARY Recent evidence suggests that lncRNAs play an integral regulatory role in numerous functions, including determination of cellular identity. We determined global expression (RNA-seq) and genome wide profiles (ChIP-seq) of histone post-translational modifications and p53 binding in human embryonic stem cells (hESCs) undergoing differentiation to define a high-confidence set of 40 lncRNAs, which are p53 transcriptional targets. We focused on lncRNAs highly expressed in pluripotent hESCs and repressed by p53 during differentiation to identify lncPRESS1 as a p53-regulated transcript that maintains hESC pluripotency in concert with core pluripotency factors. RNA-seq of hESCs depleted of lncPRESS1 revealed that lncPRESS1 controls a gene network that promotes pluripotency. Further, we found that lncPRESS1 physically interacts with SIRT6 and prevents SIRT6 chromatin localization, which maintains high levels of histone H3K56 and H3K9 acetylation at promoters of pluripotency genes. In summary, we describe a p53-regulated, pluripotency-specific lncRNA that safeguards the hESC state by disrupting SIRT6 activity.

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

“…[42][43][44][45][46] These 2 lncRNAs are investigated further to hypothesize their probable role as RNA decoys in G1-S phase transition of hESCs. However, our study could not predict lncPRESS1, a lncRNA which is already known to act as an RNA decoy by interacting with SIRT6 and induce the expressions of pluripotent genes in hESCs to maintain pluripotency 27 as well as few other lncRNAs associated with pluripotency. This is due to either absence of expression of those lncRNAs in our analysis of RNA-seq data or absence of TFs in the interactions.…”

“…Among the enriched pathways, we focused our analysis on the G1‐S cell cycle phase transition, because this is known to play a major role in ESC stemness . Moreover, there are few reports on the involvement of lncRNAs in cell cycle regulations of hESCs …”

“…38,39 Moreover, there are few reports on the involvement of lncRNAs in cell cycle regulations of hESCs. 10,27,40 Human embryonic stem cell is known to have a short G1 phase and rapid G1-S phase transition which is guided by pluripotent genes controlling stem cell pluripotency. 41 This cell cycle gets modulated FIGURE 2 The lncRNA-TFM-gene subnetwork associated with G1-S cell cycle phase transition pathway during the process of hESC differentiation into adult cells with the appearance of an elongated G1 phase and delaying in G1-S phase transition.…”

“…10 Further, studies have shown that lncRNAs play important roles in regulating hESC-specific transcriptional activation of genes by controlling posttranscriptional regulations by acting as miRNA sponge or by facilitating epigenetic modification via contributing to the functioning of chromatin modifiers. 10,22,[24][25][26][27] These suggest that lncRNAs are crucial regulators of hESC properties, although roles or modes of actions of many lncRNAs are still enigmatic in hESCs.…”

RNA-Binding Proteins as Important Regulators of Long Non-Coding RNAs in Cancer

“…Mechanisms of transcriptional regulation by lncRNAs are multifarious and can occur either in cis or in trans, meaning either closer to or further away from the lncRNA's site of transcription, respectively [6,7]. A frequent mechanism of transcriptional regulation via lncRNAs is the recruitment, or prevention of such, of components of chromatin or histone-modifying complexes, like polycomb repressive complexes or histone deacetylase complexes [11][12][13]. LncRNAs can also direct transcription factors or cofactors to promoter regions of genes and facilitate the formation of chromatin loops between distant enhancers and promoters, as observed for some eRNAs [9,[14][15][16][17].…”