TERRA regulate the transcriptional landscape of pluripotent cells through TRF1-dependent recruitment of PRC2

Abstract

The mechanisms that regulate pluripotency are still largely unknown. Here, we show that Telomere Repeat Binding Factor 1 (TRF1), a component of the shelterin complex, regulates the genome-wide binding of polycomb and polycomb H3K27me3 repressive marks to pluripotency genes, thereby exerting vast epigenetic changes that contribute to the maintenance of mouse ES cells in a naïve state. We further show that TRF1 mediates these effects by regulating TERRA, the lncRNAs transcribed from telomeres. We find that TERRAs are enriched at polycomb and stem cell genes in pluripotent cells and that TRF1 abrogation results in increased TERRA levels and in higher TERRA binding to those genes, coincidental with the induction of cell-fate programs and the loss of the naïve state. These results are consistent with a model in which TRF1-dependent changes in TERRA levels modulate polycomb recruitment to pluripotency and differentiation genes. These unprecedented findings explain why TRF1 is essential for the induction and maintenance of pluripotency.

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

“…Furthermore, a previous study has reported that EZH2 overexpression may correlate with poor prognosis in EC, but this was not found in the TCGA dataset [ 127 ]. EZH2 has been reported to interact with TERF2 and TERF2IP [ 131 ], of the shelterin complex, and also telomeric repeat-containing RNA ( TERRA ) [ 132 , 133 ]. In our survival analysis, AURKA and CCNA2 were identified as markers of unfavourable prognosis ( Table S34 ), which is supported by previous immunohistochemical studies [ 122 , 134 ].…”

Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment

“…Mutation of the TERT promoter, one of the mostly commonly found non-coding mutations in cancer (Mularoni et al, 2016;PCAWG Consortium, 2020), leads to telomerase upregulation via allelespecific epigenetic alterations involving PRC2 and DNA methylation (Leao et al, 2018;Lee et al, 2019;Stern et al, 2017). The telomeric transcript TERRA associates with PRC2, and in murine iPSCs lacking Tp53, Trf1 depletion results in TERRA-PRC2 recruitment to pluripotency genes (Marión et al, 2019;Montero et al, 2018). Thus, even in situations where telomeres are not critically eroded, epigenetics impinges on telomeres, and telomeres impinge on epigenetics.…”

Subtelomeric Transcription and its Regulation

“…In contrast to these telomere-related functions, TERRA has recently been shown to be a part of genome-wide mechanisms regulating polycomb recruitment to pluripotency and cell-fate genes in mouse embryonic stem cells [ 95 ]. Earlier observations already suggested the role of the TRF1 shelterin protein in the regulation of pluripotency and tissue reprogramming.…”

“…Inspired by these facts, Marion and colleagues (2019) assessed the genome-wide impact of TRF1 down-regulation in a murine model. They showed that upon TRF1 depletion, TERRA levels were greatly increased, correlating with enhanced association with PRC2-controlled (Polycomb Repressive Complex) genes [ 95 ]. Consequently, the lack of TRF1 decreased the expression of pluripotency genes and increased the expression of differentiation genes.…”

“…Consequently, the lack of TRF1 decreased the expression of pluripotency genes and increased the expression of differentiation genes. This study indicates that TERRA could act as a factor binding specific chromatin domains to mediate the recruitment of Polycomb proteins (SUZ12 [ 95 ]).…”