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Changes in sites of open chromatin in muscle stem cells that occur upon knockout of TRF2

ABSTRACT: Telomeric proteins are present in all mammalian cells protecting chromosomal ends and ensuring organismal homeostasis. However, it was also suggested that they have additional roles in certain tissues. Muscle stem cells (MuSCs), expressing a pivotal transcription factor Pax7, are fundamental to preserve regenerative capacity of muscle tissue. Yet, the cell autonomous mechanism that regulates Pax7 expression to maintain MuSC identity is unclear. Here, we uncover that the telomeric protein TRF2 is critical to sustain stem cell identity in adult muscles and is dynamically regulated upon injury. MuSC-specific TRF2 ablation in mice aggravates muscular dystrophy, mimicking closely the severity of the human disease. Mechanistically, TRF2 directly binds to the regulatory regions of Pax7 gene and affects its expression. These findings identify a unique non-telomeric TRF2 function essential for transcribing Pax7 gene, a master stem cell regulator of the myogenic lineage, to modulate cellular properties indispensable for stem cell maintenance.

ORGANISM(S): Mus musculus

PROVIDER: GSE264045 | GEO | 2026/08/06

REPOSITORIES: GEO

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The impact of TRF2 deletion on gene expression profile of muscle stem cells

Project description:Telomeric proteins are present in all mammalian cells protecting chromosomal ends and ensuring organismal homeostasis. However, it was also suggested that they have additional roles in certain tissues. Muscle stem cells (MuSCs), expressing a pivotal transcription factor Pax7, are fundamental to preserve regenerative capacity of muscle tissue. Yet, the cell autonomous mechanism that regulates Pax7 expression to maintain MuSC identity is unclear. Here, we uncover that the telomeric protein TRF2 is critical to sustain stem cell identity in adult muscles and is dynamically regulated upon injury. MuSC-specific TRF2 ablation in mice aggravates muscular dystrophy, mimicking closely the severity of the human disease. Mechanistically, TRF2 directly binds to the regulatory regions of Pax7 gene and affects its expression. These findings identify a unique non-telomeric TRF2 function essential for transcribing Pax7 gene, a master stem cell regulator of the myogenic lineage, to modulate cellular properties indispensable for stem cell maintenance.

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Transcriptional profiling of embryonic skeletal muscle stem/progenitor cells

Project description:Muscle stem cells (MuSC) change molecular and functional properties during development. Using a transgenic Tg:Pax7-nGFP mice, we FACS-isolated MuSC from embryonic (E12.5) and foetal (E17.5) stages to understand the differences and similarities amongst the myogenic stem/progenitor populations. Pax7-nGFP+ cells were isolated by FACS from limb buds of E12.5 and E17.5 Tg:Pax7-nGFP embryos following enzymatic digestion. Affymetrix microarrays were performed on biological triplicates.

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TRF2 Inhibition-Mediated Degradation Derepresses the Neuronal Differentiation Program

Project description:Telomere binding factor 2 (TRF2), is a protein that plays a major role in the maintenance of telomere integrity. In mitotic normal and transformed cells, TRF2 inhibition triggers a rapid telomere DNA damage response that results in cell senescence or apoptosis. Here we provide evidence that TRF2 plays a role suppressing neuronal differentiation. TRF2 interacts with the RE1-silencing transcription factor (REST) in nuclear PML protein-containing compartments of neuronal cells in vivo. Inhibition of TRF2 function with a dominant-negative form of TRF2 elicits a telomeric DNA damage response, and disrupts the TRF2-REST complex resulting in proteasomal degradation of REST. Overexpression of REST impairs the ability of DN-TRF2 to induce neuronal differentiation, indicating that enhanced degradation of REST is sufficient to account for the differentiation-inducing effect of DN-TRF2. REST degradation derepresses RE1-regulated genes (L1CAM, BDNF, b3-tubulin, syntaxin and others) resulting in morphological and functional differentiation of neurons. Our findings identify a novel interaction between the telomeric protein TRF2 and REST which regulates the molecular differentiation program of neurons. Keywords: transfection and molecular inhibition

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Transcriptional profiling of embryonic skeletal muscle stem/progenitor cells

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TRF2-ChipSeq in post mitotic cells

Project description:We report the TRF2 binding sites in post mitotic mammalian cells under TRF2 (protein level) modulation. By obtaining sequences from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of differentiated muscle cells (myotubes). Importantly we find that TRF2 levels are correlated with age (R= 0.60) making our results of importance in regards of the changes that occur in the chromatin landscape upon aging. We found multiple TRF2 binding sites that are conserved across cell types (Young et al., 2008, Simonet et al., 2011) highlighting the central role of TRF2 as a key chromatin modifier and gene regulator.

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Project description:The Telomeric repeat-binding factor 2 (TRF2) binds to TTAGGG repeats located at chromosomes ends and ensures telomere protection together with the other members of shelterin. In addition to its well-known role in telomere maintenance, TRF2 can also bind to interstitial telomeric sequences (ITS) and regulate the expression of specific genes with a consequent impact on tumor formation and progression. However, a comprehensive analysis of the impact of TRF2 on global gene expression of human cancer cells is still missing and underlying mechanisms of TRF2-mediated gene expression regulation remain to be further elucidated. Here, by performing RNA sequencing analysis, we found that TRF2 alters the expression of 717 genes involved in various cancer-related pathways. Unexpectedly, Chromatin immunoprecipitation sequencing analysis revealed, that just a small portion of Differentially Regulated genes (DEGs) are directly bound by TRF2, suggesting the existence of alternative mechanisms of TRF2-mediated gene regulation. In particular, we found that TRF2 binds to various non-coding RNA (ncRNAs) regions, including miRNA host genes. Moreover, interactomic analysis unveiled that RNA binding proteins are well represented among TRF2 interactors, supporting the involvement of TRF2 in ncRNAs-mediated mechanisms. Through the intersection of omics-analyses, we provided here experimental evidence of a multilayered mechanism of regulation where TRF2, interacting with TATA-box binding protein associated factor 15 (TAF15), regulates miR181A1 host gene and mature miR-181a-5p expression, which in turn targets S100A10, a known plasma membrane with oncogenic role. Our work shows, for the first time, a broad overview on the extratelomeric role of TRF2 in human cancer revealing, at the same time, a new axis through which TRF2 contributes to cancer progression.

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Multi-omics analyses integration reveals a novel TRF2-miR-181a-5p-S100A10 regulatory axis in colon cancer [RNA-seq]

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ZNF524 directly binds telomeres and supports their integrity via TRF2/RAP1

Project description:Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex consists of six proteins (TRF1, TRF2, RAP1, POT1, TPP1 and TIN2) and blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. While shelterin does not work autonomously, additional direct telomere binding proteins have been described to function in a supplementary role. We here describe ZNF524, a zinc finger protein that directly binds to telomeric repeats with nanomolar affinity and reveal the base-specific sequence recognition by co-crystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting the other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, we identified ZNF524 as a direct telomere binding protein and propose that ZNF524 is involved in the maintenance of telomere integrity by promoting TRF2/RAP1 subcomplex binding.

2023-10-21 | PXD024630 | Pride

ZNF524 directly binds telomeres and supports their integrity via TRF2/RAP1

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Project description:Background: The Telomeric Repeat binding Factor 2 (TRF2), a key protein involved in telomere integrity, is over-expressed in several human cancers and promotes tumor formation and progression. Recently, TRF2 has been also found outside telomeres where it can affect gene expression. Here we provide evidence that TRF2 is able to modulate the expression of microRNAs (miRNAs), small non-coding RNAs altered in human tumors. Among the miRNAs regulated by TRF2, we focused on the miR-193b-3p, an oncomiRNA that positively correlates with TRF2 expression in human colorectal cancer patients. At the mechanistic level, the control of miR-193b-3p expression requires the cooperative activity between TRF2 and the chromatin organization factor CTCF. We found that CTCF physically interacts with TRF2, thus driving the proper positioning of TRF2 on a binding site located upstream the miR-193b-3p host-gene. The binding of TRF2 on the identified region is necessary for promoting the expression of miR-193b3p which, in turn, inhibits the translation of the onco-suppressive methyltransferase SUV39H1 and promotes tumor cell proliferation. The translational relevance of the oncogenic properties of miR-193b-3p was confirmed in patients, in whom the association between TRF2 and miR-193b-3p has a prognostic value.

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