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双重DNA去甲基化机制实现了由先驱因子PAX7驱动的表观遗传记忆。

Dual DNA demethylation mechanisms implement epigenetic memory driven by the pioneer factor PAX7.

作者信息

Harris Juliette, Mayran Alexandre, Gouhier Arthur, Gauthier Yves, Sleiman Nawal Hajj, Merabet Samir, Dukatz Michael, Bashtrykov Pavel, Jeltsch Albert, Djambazian Haig, Chen Shu-Huang, Balsalobre Aurelio, Drouin Jacques

机构信息

Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal, Montréal H2W1R7, Canada.

Institut de Génomique Fonctionnelle de Lyon, CNRS UMR5242, École Normale Supérieure de Lyon, Université Lyon I, Lyon 69007, France.

出版信息

Sci Adv. 2025 May 16;11(20):eadu6632. doi: 10.1126/sciadv.adu6632.

DOI:10.1126/sciadv.adu6632
PMID:40378211
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12083534/
Abstract

Pioneer transcription factors have the unique ability to open chromatin at enhancers to implement new cell fates. They also provide epigenetic memory through demethylation of enhancer DNA, but the underlying mechanisms remain unclear. We now show that the pioneer paired box 7 (PAX7) triggers DNA demethylation using two replication-dependent mechanisms, including direct PAX7 interaction with the E3 ubiquitin-protein ligase (UHRF1)-DNA methyltransferase 1 (DNMT1) complex that is responsible for DNA methylation maintenance. PAX7 binds to UHRF1 and prevents its interaction with DNMT1, thus blocking activation of its enzyme activity. The ten-eleven translocation DNA dioxygenase (TET) DNA demethylases also contribute to the replication-dependent loss of DNA methylation. Thus, PAX7 hijacks UHRF1 to block activation of DNMT1 after replication, leading to loss of DNA methylation by dilution, and the process is assisted by the action of TET demethylases.

摘要

先驱转录因子具有独特的能力，可在增强子处打开染色质以实现新的细胞命运。它们还通过增强子DNA的去甲基化提供表观遗传记忆，但其潜在机制仍不清楚。我们现在表明，先驱配对盒7（PAX7）使用两种复制依赖性机制触发DNA去甲基化，包括PAX7与负责DNA甲基化维持的E3泛素蛋白连接酶（UHRF1）-DNA甲基转移酶1（DNMT1）复合物直接相互作用。PAX7与UHRF1结合并阻止其与DNMT1相互作用，从而阻断其酶活性的激活。十一-十一易位DNA双加氧酶（TET）DNA去甲基化酶也有助于复制依赖性DNA甲基化的丧失。因此，PAX7劫持UHRF1以在复制后阻断DNMT1的激活，导致DNA甲基化因稀释而丧失，并且该过程由TET去甲基化酶的作用辅助。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e564/12083534/414e747227a0/sciadv.adu6632-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e564/12083534/55aa29ef067a/sciadv.adu6632-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e564/12083534/0bafa369b8ab/sciadv.adu6632-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e564/12083534/e31af79c6f6f/sciadv.adu6632-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e564/12083534/414e747227a0/sciadv.adu6632-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e564/12083534/55aa29ef067a/sciadv.adu6632-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e564/12083534/0bafa369b8ab/sciadv.adu6632-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e564/12083534/e31af79c6f6f/sciadv.adu6632-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e564/12083534/414e747227a0/sciadv.adu6632-f4.jpg

相似文献

[1]
Dual DNA demethylation mechanisms implement epigenetic memory driven by the pioneer factor PAX7.

Sci Adv. 2025-5-16

[2]
Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells.

Nat Commun. 2024-4-5

[3]
UHRF1 ubiquitin ligase activity supports the maintenance of low-density CpG methylation.

Nucleic Acids Res. 2024-12-11

[4]
RAD51 plays critical roles in DNMT1-mediated maintenance methylation of genomic DNA by dually regulating the ubiquitin ligase UHRF1.

Proc Natl Acad Sci U S A. 2024-12-10

[5]
SET8 prevents excessive DNA methylation by methylation-mediated degradation of UHRF1 and DNMT1.

Nucleic Acids Res. 2019-9-26

[6]
A role for LSH in facilitating DNA methylation by DNMT1 through enhancing UHRF1 chromatin association.

Nucleic Acids Res. 2020-12-2

[7]
Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma.

J Exp Clin Cancer Res. 2025-1-15

[8]
A Bifunctional Role for the UHRF1 UBL Domain in the Control of Hemi-methylated DNA-Dependent Histone Ubiquitylation.

Mol Cell. 2018-11-1

[9]
Enhanced processivity of Dnmt1 by monoubiquitinated histone H3.

Genes Cells. 2019-12-3

[10]
Proteomic Analysis of Azacitidine-Induced Degradation Profiles Identifies Multiple Chromatin and Epigenetic Regulators Including Uhrf1 and Dnmt1 as Sensitive to Azacitidine.

J Proteome Res. 2019-2-7

本文引用的文献

[1]
Pioneer factor Pax7 initiates two-step cell-cycle-dependent chromatin opening.

Nat Struct Mol Biol. 2024-1

[2]
Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy.

Cell Rep. 2023-8-29

[3]
Chromatin opening ability of pioneer factor Pax7 depends on unique isoform and C-terminal domain.

Nucleic Acids Res. 2023-8-11

[4]
On the accuracy of the epigenetic copy machine: comprehensive specificity analysis of the DNMT1 DNA methyltransferase.

Nucleic Acids Res. 2023-7-21

[5]
Pronounced sequence specificity of the TET enzyme catalytic domain guides its cellular function.

Sci Adv. 2022-9-9

[6]
Pioneer factors as master regulators of the epigenome and cell fate.

Nat Rev Mol Cell Biol. 2022-7

[7]
Flanking sequences influence the activity of TET1 and TET2 methylcytosine dioxygenases and affect genomic 5hmC patterns.

Commun Biol. 2022-1-24

[8]
Pax7 pioneer factor action requires both paired and homeo DNA binding domains.

Nucleic Acids Res. 2021-7-21

[9]
Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish.

Commun Biol. 2021-6-25

[10]
FoxA-dependent demethylation of DNA initiates epigenetic memory of cellular identity.

Dev Cell. 2021-3-8

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