Chromatin lncRNA Platr10 controls stem cell pluripotency by coordinating an intrachromosomal regulatory network

Abstract

Background A specific 3-dimensional intrachromosomal architecture of core stem cell factor genes is required to reprogram a somatic cell into pluripotency. As little is known about the epigenetic readers that orchestrate this architectural remodeling, we used a novel chromatin RNA in situ reverse transcription sequencing (CRIST-seq) approach to profile long noncoding RNAs (lncRNAs) in the Oct4 promoter. Results We identify Platr10 as an Oct4 - Sox2 binding lncRNA that is activated in somatic cell reprogramming. Platr10 is essential for the maintenance of pluripotency, and lack of this lncRNA causes stem cells to exit from pluripotency. In fibroblasts, ectopically expressed Platr10 functions in trans to activate core stem cell factor genes and enhance pluripotent reprogramming. Using RNA reverse transcription-associated trap sequencing (RAT-seq), we show that Platr10 interacts with multiple pluripotency-associated genes, including Oct4, Sox2, Klf4, and c-Myc, which have been extensively used to reprogram somatic cells. Mechanistically, we demonstrate that Platr10 helps orchestrate intrachromosomal promoter-enhancer looping and recruits TET1, the enzyme that actively induces DNA demethylation for the initiation of pluripotency. We further show that Platr10 contains an Oct4 binding element that interacts with the Oct4 promoter and a TET1-binding element that recruits TET1. Mutation of either of these two elements abolishes Platr10 activity. Conclusion These data suggest that Platr10 functions as a novel chromatin RNA molecule to control pluripotency in trans by modulating chromatin architecture and regulating DNA methylation in the core stem cell factor network.

LncRNA-mediated DNA methylation: an emerging mechanism in cancer and beyond

“…Similarly, Du et al . identified two motifs in lncRNA Platr10 that interact with Oct4 promoter and TET1 respectively, thus inducing TET1- mediated DNA demethylation at specific site [ 101 ]. A research by Zhou et al .…”

Dynamic Transcriptome Profiling Reveals LncRNA-Centred Regulatory Networks in the Modulation of Pluripotency

“…As canonical non-coding regulators of cell fate in the nucleus, Xist , Lncenc1 , and Gas5 , were included in the subgroup of polyadenylated lncRNAs specifically expressed in ESC ( Figure 2B ), further suggesting the accuracy and validity of our lncRNA-seq data. Intriguingly, this cluster also contained a large number of members from two lncRNA families, Platr and Snhg , some of which have been reported to regulate the stem cell fate transition ( Bergmann et al, 2015 ; Lu et al, 2019 ; Li et al, 2020 ; Du et al, 2021 ; Yan et al, 2021 ).…”

Long Noncoding RNA Mediated Regulation in Human Embryogenesis, Pluripotency, and Reproduction

“…Pluripotent stem cells (PSCs) cultured in vitro provide a unique model for studying the molecular mechanisms of human embryogenesis [ 40 ] and are considered the seed cells to differentiate into functional cells for cellular therapeutics [ 41 ]. The core regulatory network for self-renewal and pluripotency involves transcription factors, chromatin modifiers, and lncRNAs [ 42 , 43 ]( Figure 3 ). PSCs express a characteristic set of lncRNAs that interact with the other members of the core regulatory network to (1) regulate gene expression, (2) modulate signaling pathways, (3) maintain epigenetic signatures, and (4) direct differentiation.…”