TY - JOUR
T1 - Telomere repeat-binding factor 2 binds extensively to extra-telomeric G-quadruplexes and regulates the epigenetic status of several gene promoters
AU - Mukherjee, Ananda Kishore
AU - Sharma, Shalu
AU - Bagri, Sulochana
AU - Kutum, Rintu
AU - Kumar, Pankaj
AU - Hussain, Asgar
AU - Singh, Prateek
AU - Saha, Dhurjhoti
AU - Kar, Anirban
AU - Dash, Debasis
AU - Chowdhury, Shantanu
N1 - Funding Information:
From the ‡Integrative and Functional Biology Unit, §Academy of Scientific and Innovative Research (AcSIR), ¶G.N.R. Knowledge Centre for Genome Informatics, and ‖CSIR Ayurgenomics Unit-TRISUTRA, Council of Scientific and Industrial Research (CSIR)-Institute of Genomics and Integrative Biology (IGIB), Mathura Road, New Delhi 110025, India
Funding Information:
This work was supported by research fellowships from the Council of Scien-tific and Industrial Research (CSIR) (to A. K. M., S. S., and P. K.) and Wellcome Trust/Department of Biotechnology (DBT) India Alliance (to D. S.) and DBT (to S. B.). This work was supported by the Wellcome Trust/DBT India Alli-ance Fellowship (Grant 500127/Z/09/Z) (to S. C.) and a research grant from CSIR (GENCODE). The authors declare that they have no conflicts of interest with the contents of this article. Author’s Choice—Final version open access under the terms of the Creative Commons CC-BY license. This article was selected as one of our Editors’ Picks. This article contains Figs. S1–S5 and additional supporting information. Raw sequencing data reads for ChIP-Seq are publicly available under the SRA study (accession number SRA 304653 (SRX1334027)). 1 Both authors contributed equally to this work. 2 Recipient of a fellowship from the TRISUTRA project. 3 Recipient of a fellowship from DBT-BINC. 4To whom correspondence should be addressed. E-mail: shantanuc@ igib.res.in.
Publisher Copyright:
© 2019 Mukherjee et al.
PY - 2019/11/22
Y1 - 2019/11/22
N2 - The role of the telomere repeat-binding factor 2 (TRF2) in telomere maintenance is well-established. However, recent findings suggest that TRF2 also functions outside telomeres, but relatively little is known about this function. Herein, using genome-wide ChIP-Seq assays of TRF2-bound chromatin from HT1080 fibrosarcoma cells, we identified thousands of TRF2-binding sites within the extra-telomeric genome. In light of this observation, we asked how TRF2 occupancy is organized within the genome. Interestingly, we found that extra-telomeric TRF2 sites throughout the genome are enriched in potential G-quadruplex-forming DNA sequences. Furthermore, we validated TRF2 occupancy at several promoter G-quadruplex motifs, which did adopt quadruplex forms in solution. TRF2 binding altered expression and the epigenetic state of several target promoters, indicated by histone modifications resulting in transcriptional repression of eight of nine genes investigated here. Furthermore, TRF2 occupancy and target gene expression were also sensitive to the well-known intracellular G-quadruplex-binding ligand 360A. Together, these results reveal an extensive genome-wide association of TRF2 outside telomeres and that it regulates gene expression in a G-quadruplex-dependent fashion.
AB - The role of the telomere repeat-binding factor 2 (TRF2) in telomere maintenance is well-established. However, recent findings suggest that TRF2 also functions outside telomeres, but relatively little is known about this function. Herein, using genome-wide ChIP-Seq assays of TRF2-bound chromatin from HT1080 fibrosarcoma cells, we identified thousands of TRF2-binding sites within the extra-telomeric genome. In light of this observation, we asked how TRF2 occupancy is organized within the genome. Interestingly, we found that extra-telomeric TRF2 sites throughout the genome are enriched in potential G-quadruplex-forming DNA sequences. Furthermore, we validated TRF2 occupancy at several promoter G-quadruplex motifs, which did adopt quadruplex forms in solution. TRF2 binding altered expression and the epigenetic state of several target promoters, indicated by histone modifications resulting in transcriptional repression of eight of nine genes investigated here. Furthermore, TRF2 occupancy and target gene expression were also sensitive to the well-known intracellular G-quadruplex-binding ligand 360A. Together, these results reveal an extensive genome-wide association of TRF2 outside telomeres and that it regulates gene expression in a G-quadruplex-dependent fashion.
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U2 - 10.1074/jbc.RA119.008687
DO - 10.1074/jbc.RA119.008687
M3 - Review article
C2 - 31575660
AN - SCOPUS:85075580743
SN - 0021-9258
VL - 294
SP - 17709
EP - 17722
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 47
ER -