Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells

• Published in: Nature communications 2021-02, Vol.12 (1), p.1097-1097, Article 1097
• Main Authors: Kim, Chuna, Sung, Sanghyun, Kim, Jong-Seo, Lee, Hyunji, Jung, Yoonseok, Shin, Sanghee, Kim, Eunkyeong, Seo, Jenny J., Kim, Jun, Kim, Daeun, Niida, Hiroyuki, Kim, V. Narry, Park, Daechan, Lee, Junho
• Format: Article
• Language: English
• Subjects: 45/15; 45/23; 45/77; 45/91; 631/1647/2217; 631/80/103/560; 82/1; 82/58; Animals; Chromosomes; Deoxyribonucleic acid; DNA; DNA damage; DNA-Binding Proteins - genetics; Embryo cells; Epigenomics - methods; HEK293 Cells; Histones; Humanities and Social Sciences; Humans; Maintenance; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; multidisciplinary; Proteomics; Proteomics - methods; Recombination; Repetitive Sequences, Nucleic Acid - genetics; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Sequence Analysis, RNA - methods; Single-Cell Analysis - methods; Stability; Stem cell transplantation; Stem cells; Telomerase; Telomerase - genetics; Telomerase - metabolism; Telomere - enzymology; Telomere - genetics; Telomere Homeostasis - genetics; Telomeres; Transcription; Transcription Factors - genetics; Yeast
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21341-x

Telomeres are part of a highly refined system for maintaining the stability of linear chromosomes. Most telomeres rely on simple repetitive sequences and telomerase enzymes to protect chromosomal ends; however, in some species or telomerase-defective situations, an alternative lengthening of telomeres (ALT) mechanism is used. ALT mainly utilises recombination-based replication mechanisms and the constituents of ALT-based telomeres vary depending on models. Here we show that mouse telomeres can exploit non-telomeric, unique sequences in addition to telomeric repeats. We establish that a specific subtelomeric element, the mouse template for ALT (mTALT), is used for repairing telomeric DNA damage as well as for composing portions of telomeres in ALT-dependent mouse embryonic stem cells. Epigenomic and proteomic analyses before and after ALT activation reveal a high level of non-coding mTALT transcripts despite the heterochromatic nature of mTALT-based telomeres. After ALT activation, the increased HMGN1, a non-histone chromosomal protein, contributes to the maintenance of telomere stability by regulating telomeric transcription. These findings provide a molecular basis to study the evolution of new structures in telomeres. Telomeres can be maintained by a telomerase-independent mechanism called an alternative lengthening of telomeres (ALT). Here the authors use mouse Terc (telomerase RNA) knockout embryonic cells and provide longitudinal analysis of ALT telomeres maintained with non-telomeric sequences.