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bioRxiv · 10.1101/2025.10.29.685418

TET1 non-catalytic activity shapes the chromatin landscape that directs de novo methylation establishment in the male germline

Prasasya, R. D.·Kim, J. J.·Liu, Z.·Kohli, R. M.·Bartolomei, M. S.
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Abstract

In the germline, DNA methylation is globally erased in primordial germ cells (PGCs), enabling establishment of sex-specific methylomes in prospermatogonia or oocytes. The catalytic activity of TET1 is required for complete demethylation in PGCs, yet sperm from Tet1-/- mice display methylation defects not explained by incomplete erasure. Instead, these defects arise from abnormal de novo methylation during development, coinciding with erosion of H3K4me3, a chromatin modification that blocks DNMT3A/3L. Using a catalytically inactive Tet1HxD mouse line, we demonstrate a non-catalytic role of TET1 in promoting H3K4me3 deposition and protecting a subset of sperm hypomethylated regions from aberrant methylation in prospermatogonia.

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Prasasya, R. D., Kim, J. J., Liu, Z., Kohli, R. M., Bartolomei, M. S.. 2025-10-30. TET1 non-catalytic activity shapes the chromatin landscape that directs de novo methylation establishment in the male germline. https://doi.org/10.1101/2025.10.29.685418

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