Pronounced sequence specificity of the TET enzyme catalytic domain guides its cellular function

Ravichandran, Mirunalini, Rafalski, Dominik, Davies, Claudia I., Ortega-Recalde, Oscar, Nan, Xinsheng ORCID: https://orcid.org/0000-0002-0865-7934, Glanfield, Cassandra R., Kotter, Annika, Misztal, Katarzyna, Wang, Andrew H., Wojciechowski, Marek, Razew, Michal, Mayyas, Issam M., Kardailsky, Olga, Schwartz, Uwe, Zembrzycki, Krzysztof, Morison, Ian M., Helm, Mark, Weichenhan, Dieter, Jurkowska, Renata Z. ORCID: https://orcid.org/0000-0002-4507-2222, Krueger, Felix, Plass, Christoph, Zacharias, Martin, Bochtler, Matthias, Hore, Timothy A. and Jurkowski, Tomasz P. ORCID: https://orcid.org/0000-0002-2012-0240 2022. Pronounced sequence specificity of the TET enzyme catalytic domain guides its cellular function. Science Advances 8 (36) 10.1126/sciadv.abm2427

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Abstract

TET (ten-eleven translocation) enzymes catalyze the oxidation of 5-methylcytosine bases in DNA, thus driving active and passive DNA demethylation. Here, we report that the catalytic domain of mammalian TET enzymes favor CGs embedded within basic helix-loop-helix and basic leucine zipper domain transcription factor–binding sites, with up to 250-fold preference in vitro. Crystal structures and molecular dynamics calculations show that sequence preference is caused by intrasubstrate interactions and CG flanking sequence indirectly affecting enzyme conformation. TET sequence preferences are physiologically relevant as they explain the rates of DNA demethylation in TET-rescue experiments in culture and in vivo within the zygote and germ line. Most and least favorable TET motifs represent DNA sites that are bound by methylation-sensitive immediate-early transcription factors and octamer-binding transcription factor 4 (OCT4), respectively, illuminating TET function in transcriptional responses and pluripotency support.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	American Association for the Advancement of Science
ISSN:	2375-2548
Date of First Compliant Deposit:	12 September 2022
Date of Acceptance:	26 July 2022
Last Modified:	17 May 2023 22:04
URI:	https://orca.cardiff.ac.uk/id/eprint/152480

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