Isoform-specific and ubiquitination dependent recruitment of Tet1 to replicating heterochromatin modulates methylcytosine oxidation

• Published in: Nature communications Vol. 13; no. 1; p. 5173
• Main Authors: Arroyo, María, Hastert, Florian D., Zhadan, Andreas, Schelter, Florian, Zimbelmann, Susanne, Rausch, Cathia, Ludwig, Anne K., Carell, Thomas, Cardoso, M. Cristina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 14; 14/19; 14/35; 14/63; 38; 38/15; 38/23; 42; 45; 5-Methylcytosine - metabolism; 631/337/176/1988; 631/80/2373; 631/80/386; 631/80/458/582; Animals; Catalytic activity; CCAAT-Enhancer-Binding Proteins - genetics; Cell cycle; Chromatin; Cytosine; Cytosine - metabolism; Deoxyribonucleic acid; Dioxygenases - metabolism; DNA; DNA biosynthesis; DNA damage; DNA Methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epigenetics; Gene expression; Heterochromatin; Heterochromatin - genetics; Humanities and Social Sciences; Humans; Localization; Mice; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; multidisciplinary; Oxidation; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Replication; Science; Science (multidisciplinary); Tumors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Zinc finger proteins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32799-8

Oxidation of the epigenetic DNA mark 5-methylcytosine by Tet dioxygenases is an established route to diversify the epigenetic information, modulate gene expression and overall cellular (patho-)physiology. Here, we demonstrate that Tet1 and its short isoform Tet1s exhibit distinct nuclear localization during DNA replication resulting in aberrant cytosine modification levels in human and mouse cells. We show that Tet1 is tethered away from heterochromatin via its zinc finger domain, which is missing in Tet1s allowing its targeting to these regions. We find that Tet1s interacts with and is ubiquitinated by CRL4(VprBP). The ubiquitinated Tet1s is then recognized by Uhrf1 and recruited to late replicating heterochromatin. This leads to spreading of 5-methylcytosine oxidation to heterochromatin regions, LINE 1 activation and chromatin decondensation. In summary, we elucidate a dual regulation mechanism of Tet1, contributing to the understanding of how epigenetic information can be diversified by spatio-temporal directed Tet1 catalytic activity. A short isoform of the Tet1 enzyme (Tet1s) that oxidizes the DNA 5-methylcytosine (5mC) mark is overexpressed in tumors. Here the authors show Tet1s, but not full length Tet1, changes localization over the cell cycle upon ubiquitination and Uhrf1 interaction and is targeted to heterochromatin during S-phase. This leads to 5mC oxidation and loss of DNA methylation in heterochromatin.