Dynamic TET1 repression coordinates activation of macroH2A.2-poised bivalent genes during neuroectoderm differentiation
- 1University of California, San Francisco, School of Medicine
Abstract
Cell state transitions involve changes in gene expression programs in conjunction with epigenetic regulation occurring in chromatin. Bivalent chromatin, marked by overlapping active H3K4me3 and repressive H3K27me3, poises key developmental genes during pluripotency for cell type-specific activation during differentiation. However, the molecular mechanisms that activate bivalent genes during lineage commitment remain poorly understood. Here, we elucidate how the cytosine dioxygenase TET1 promotes neuroectoderm differentiation through dynamic chromatin binding and a non-catalytic repressor function. Through a hypothesis-free screen for TET1 chromatin complex partners, we find that TET1 physically interacts with macroH2A.2 and H2A.X on chromatin. Integrated multi-omic analyses reveal that the non-catalytic repressor function of TET1 and a novel activating function of the H2A variant macroH2A.2 together promote a poised transcriptional state within bivalent chromatin during pluripotency. Upon pluripotency exit, TET1 disengages from macroH2A.2-marked early neuroectoderm genes to permit their activation, while remaining bound as a repressor at mesoendoderm and late neural genes to prevent alternative cell state transitions. Furthermore, TET1 retention at accessible primed enhancers supports neural program activation. Together, our findings reveal a noncanonical functional interplay within bivalent chromatin between TET1 and macroH2A.2 that maintains a poised state during pluripotency and predicts selective gene activation during neuroectoderm specification.
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BibTeX
@misc{terry2026dynamic,
title = {{Dynamic TET1 repression coordinates activation of macroH2A.2-poised bivalent genes during neuroectoderm differentiation}},
author = {B. Terry and C. Stapel and F. Santos and J. Kent and K. Kishore and C. D'Santos and I. Chambers and A. Parry and W. Reik},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.17.759687},
url = {https://www.biorxiv.org/content/10.64898/2026.10.17.759687v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Dynamic TET1 repression coordinates activation of macroH2A.2-poised bivalent genes during neuroectoderm differentiation
AU - B. Terry
AU - C. Stapel
AU - F. Santos
AU - J. Kent
AU - K. Kishore
AU - C. D'Santos
AU - I. Chambers
AU - A. Parry
AU - W. Reik
PY - 2026
DA - 2026/10/17
PB - bioRxiv
DO - 10.64898/2026.10.17.759687
UR - https://www.biorxiv.org/content/10.64898/2026.10.17.759687v1
AB - Cell state transitions involve changes in gene expression programs in conjunction with epigenetic regulation occurring in chromatin. Bivalent chromatin, marked by overlapping active H3K4me3 and repressive H3K27me3, poises key developmental genes during pluripotency for cell type-specific activation during differentiation. However, the molecular mechanisms that activate bivalent genes during lineage commitment remain poorly understood. Here, we elucidate how the cytosine dioxygenase TET1 promotes neuroectoderm differentiation through dynamic chromatin binding and a non-catalytic repressor function. Through a hypothesis-free screen for TET1 chromatin complex partners, we find that TET1 physically interacts with macroH2A.2 and H2A.X on chromatin. Integrated multi-omic analyses reveal that the non-catalytic repressor function of TET1 and a novel activating function of the H2A variant macroH2A.2 together promote a poised transcriptional state within bivalent chromatin during pluripotency. Upon pluripotency exit, TET1 disengages from macroH2A.2-marked early neuroectoderm genes to permit their activation, while remaining bound as a repressor at mesoendoderm and late neural genes to prevent alternative cell state transitions. Furthermore, TET1 retention at accessible primed enhancers supports neural program activation. Together, our findings reveal a noncanonical functional interplay within bivalent chromatin between TET1 and macroH2A.2 that maintains a poised state during pluripotency and predicts selective gene activation during neuroectoderm specification.
ER -