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

María Arroyo, Florian D. Hastert (), Andreas Zhadan, Florian Schelter, Susanne Zimbelmann, Cathia Rausch, Anne K. Ludwig, Thomas Carell and M. Cristina Cardoso ()
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María Arroyo: Technical University of Darmstadt
Florian D. Hastert: Technical University of Darmstadt
Andreas Zhadan: Technical University of Darmstadt
Florian Schelter: Ludwig Maximilians University
Susanne Zimbelmann: Technical University of Darmstadt
Cathia Rausch: Technical University of Darmstadt
Anne K. Ludwig: Technical University of Darmstadt
Thomas Carell: Ludwig Maximilians University
M. Cristina Cardoso: Technical University of Darmstadt

Nature Communications, 2022, vol. 13, issue 1, 1-28

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32799-8

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