NuRD-enabled CTCF-TET crosstalk orchestrates epigenome reprogramming and genome architecture

Wenju Sun; Nan Wu; Minhui Xia; Yilin Pan; Meishuo Liu; Shaorong Fan; Jueheng Wang; Yitian Zeng; Ligang Fan; Jie Chen; Guopan Liu; Huanyu Yan; Yunjiang Qiu; Yang Xie; Zenan Jiang; Fulin Chen; Yimeng Yin; Jilin Zhang; Lei Li; Wei Xie; Haifeng Wang; Liang Zhang; Miao Yu; Xi Wang; Jian Yan

doi:10.1016/j.molcel.2026.05.010

NuRD-enabled CTCF-TET crosstalk orchestrates epigenome reprogramming and genome architecture

Wenju Sun (Co-first Author)
, Nan Wu (Co-first Author)
, Minhui Xia (Co-first Author)
, Yilin Pan
, Meishuo Liu
, Shaorong Fan
, Jueheng Wang
, Yitian Zeng
, Ligang Fan
, Jie Chen
, Guopan Liu
, Huanyu Yan
, Yunjiang Qiu
, Yang Xie
, Zenan Jiang
, Fulin Chen
, Yimeng Yin
, Jilin Zhang
, Lei Li
, Wei Xie

Haifeng Wang, Liang Zhang^*, Miao Yu^*, Xi Wang^*, Jian Yan^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

Abstract

CCCTC-binding factor (CTCF) is an evolutionarily conserved transcription factor with diverse regulatory roles. Its binding sites exhibit highly ordered nucleosomes and DNA hypomethylation, but how this epigenetic landscape is established remains unclear. In this study, we develop a GpC methylation-assisted tracing (G-MAT) approach to investigate the interplay between DNA methylation and CTCF binding at a base-pair resolution, which reveals that CTCF-chromatin interaction frequently coincides with methylated DNA, which is likely mediated by the nucleosome remodeling and deacetylase (NuRD) complex. We show that NuRD is indispensable for CTCF's chromatin binding, emerging as a regulator of high-order genome architecture. Mechanistically, NuRD facilitates CTCF to interact with TET methylcytosine dioxygenase to maintain adjacent DNA hypomethylation, which is essential for activation of nearby genes. Notably, embryonic stem cells lacking NuRD exhibit impaired lineage commitment. Together, our study unravels a mechanism that elucidates the crosstalk between CTCF binding and the epigenome, with NuRD playing a crucial role as a mediator.

Original language	English
Pages (from-to)	2617-2634
Number of pages	18
Journal	Molecular Cell
Volume	86
Issue number	13
Online published	1 Jun 2026
DOIs	https://doi.org/10.1016/j.molcel.2026.05.010
Publication status	Published - 2 Jul 2026

Funding

This study was financially supported by the National Natural Science Foundation of China (32270634, 92374117, 32270571, and 31900443), the Shenzhen Medical Research Fund (B2302027 and D2501003), the Shaanxi Academy of Fundamental Sciences (22JHZ009), the Natural Science Foundation of Guangdong Province (2024A1515012685), the Research Grants Council of Hong Kong (11101022, 11101025, 11102322, 11104422, C1024-22GF, T12-101/23-N, and C1041-24EF), the Innovation and Technology Fund of Hong Kong (ITS/087/22), the Shaanxi Innovation Capability Support Program (2024RS-CXTD-85), the Start Fund for Specially Appointed Professor of Jiangsu Province (X.W.), the Shenzhen Science and Technology Innovation Commission (JCYJ20210324133812034), the CAS Youth Interdisciplinary Team (M.Y.), the City University of Hong Kong (7006043), and the State Key Laboratory of Reproductive Medicine and Offspring Health (SKLRM-2025B3).

RGC Funding Information

RGC-funded

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Sun, W., Wu, N., Xia, M., Pan, Y., Liu, M., Fan, S., Wang, J., Zeng, Y., Fan, L., Chen, J., Liu, G., Yan, H., Qiu, Y., Xie, Y., Jiang, Z., Chen, F., Yin, Y., Zhang, J., Li, L., ... Yan, J. (2026). NuRD-enabled CTCF-TET crosstalk orchestrates epigenome reprogramming and genome architecture. Molecular Cell, 86(13), 2617-2634. https://doi.org/10.1016/j.molcel.2026.05.010

@article{0910fc56d5d4456da67dd379008873e0,

title = "NuRD-enabled CTCF-TET crosstalk orchestrates epigenome reprogramming and genome architecture",

abstract = "CCCTC-binding factor (CTCF) is an evolutionarily conserved transcription factor with diverse regulatory roles. Its binding sites exhibit highly ordered nucleosomes and DNA hypomethylation, but how this epigenetic landscape is established remains unclear. In this study, we develop a GpC methylation-assisted tracing (G-MAT) approach to investigate the interplay between DNA methylation and CTCF binding at a base-pair resolution, which reveals that CTCF-chromatin interaction frequently coincides with methylated DNA, which is likely mediated by the nucleosome remodeling and deacetylase (NuRD) complex. We show that NuRD is indispensable for CTCF's chromatin binding, emerging as a regulator of high-order genome architecture. Mechanistically, NuRD facilitates CTCF to interact with TET methylcytosine dioxygenase to maintain adjacent DNA hypomethylation, which is essential for activation of nearby genes. Notably, embryonic stem cells lacking NuRD exhibit impaired lineage commitment. Together, our study unravels a mechanism that elucidates the crosstalk between CTCF binding and the epigenome, with NuRD playing a crucial role as a mediator. {\textcopyright} 2026 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.",

author = "Wenju Sun and Nan Wu and Minhui Xia and Yilin Pan and Meishuo Liu and Shaorong Fan and Jueheng Wang and Yitian Zeng and Ligang Fan and Jie Chen and Guopan Liu and Huanyu Yan and Yunjiang Qiu and Yang Xie and Zenan Jiang and Fulin Chen and Yimeng Yin and Jilin Zhang and Lei Li and Wei Xie and Haifeng Wang and Liang Zhang and Miao Yu and Xi Wang and Jian Yan",

year = "2026",

month = jul,

day = "2",

doi = "10.1016/j.molcel.2026.05.010",

language = "English",

volume = "86",

pages = "2617--2634",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "13",

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Sun, W, Wu, N, Xia, M, Pan, Y, Liu, M, Fan, S, Wang, J, Zeng, Y, Fan, L, Chen, J, Liu, G, Yan, H, Qiu, Y, Xie, Y, Jiang, Z, Chen, F, Yin, Y, Zhang, J, Li, L, Xie, W, Wang, H, Zhang, L, Yu, M, Wang, X & Yan, J 2026, 'NuRD-enabled CTCF-TET crosstalk orchestrates epigenome reprogramming and genome architecture', Molecular Cell, vol. 86, no. 13, pp. 2617-2634. https://doi.org/10.1016/j.molcel.2026.05.010

TY - JOUR

T1 - NuRD-enabled CTCF-TET crosstalk orchestrates epigenome reprogramming and genome architecture

AU - Sun, Wenju

AU - Wu, Nan

AU - Xia, Minhui

AU - Pan, Yilin

AU - Liu, Meishuo

AU - Fan, Shaorong

AU - Wang, Jueheng

AU - Zeng, Yitian

AU - Fan, Ligang

AU - Chen, Jie

AU - Liu, Guopan

AU - Yan, Huanyu

AU - Qiu, Yunjiang

AU - Xie, Yang

AU - Jiang, Zenan

AU - Chen, Fulin

AU - Yin, Yimeng

AU - Zhang, Jilin

AU - Li, Lei

AU - Xie, Wei

AU - Wang, Haifeng

AU - Zhang, Liang

AU - Yu, Miao

AU - Wang, Xi

AU - Yan, Jian

PY - 2026/7/2

Y1 - 2026/7/2

N2 - CCCTC-binding factor (CTCF) is an evolutionarily conserved transcription factor with diverse regulatory roles. Its binding sites exhibit highly ordered nucleosomes and DNA hypomethylation, but how this epigenetic landscape is established remains unclear. In this study, we develop a GpC methylation-assisted tracing (G-MAT) approach to investigate the interplay between DNA methylation and CTCF binding at a base-pair resolution, which reveals that CTCF-chromatin interaction frequently coincides with methylated DNA, which is likely mediated by the nucleosome remodeling and deacetylase (NuRD) complex. We show that NuRD is indispensable for CTCF's chromatin binding, emerging as a regulator of high-order genome architecture. Mechanistically, NuRD facilitates CTCF to interact with TET methylcytosine dioxygenase to maintain adjacent DNA hypomethylation, which is essential for activation of nearby genes. Notably, embryonic stem cells lacking NuRD exhibit impaired lineage commitment. Together, our study unravels a mechanism that elucidates the crosstalk between CTCF binding and the epigenome, with NuRD playing a crucial role as a mediator. © 2026 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

AB - CCCTC-binding factor (CTCF) is an evolutionarily conserved transcription factor with diverse regulatory roles. Its binding sites exhibit highly ordered nucleosomes and DNA hypomethylation, but how this epigenetic landscape is established remains unclear. In this study, we develop a GpC methylation-assisted tracing (G-MAT) approach to investigate the interplay between DNA methylation and CTCF binding at a base-pair resolution, which reveals that CTCF-chromatin interaction frequently coincides with methylated DNA, which is likely mediated by the nucleosome remodeling and deacetylase (NuRD) complex. We show that NuRD is indispensable for CTCF's chromatin binding, emerging as a regulator of high-order genome architecture. Mechanistically, NuRD facilitates CTCF to interact with TET methylcytosine dioxygenase to maintain adjacent DNA hypomethylation, which is essential for activation of nearby genes. Notably, embryonic stem cells lacking NuRD exhibit impaired lineage commitment. Together, our study unravels a mechanism that elucidates the crosstalk between CTCF binding and the epigenome, with NuRD playing a crucial role as a mediator. © 2026 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

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UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-105040520057&origin=recordpage

U2 - 10.1016/j.molcel.2026.05.010

DO - 10.1016/j.molcel.2026.05.010

M3 - RGC 21 - Publication in refereed journal

C2 - 42225060

SN - 1097-2765

VL - 86

SP - 2617

EP - 2634

JO - Molecular Cell

JF - Molecular Cell

IS - 13

ER -

NuRD-enabled CTCF-TET crosstalk orchestrates epigenome reprogramming and genome architecture

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GRF: Dissect Mitochondrial Extracellular Vesicles in Dermatomyositis

TBRS: Single-Cell Multi-Omics Study of Atherosclerotic Vascular Disease: Narrowing the Gap Between Bench and Bedside

GRF: Delineating the Mechanisms of DANCR-Rac1 in Triple-negative Breast Cancer Invasion and Metastasis

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NuRD-enabled CTCF-TET crosstalk orchestrates epigenome reprogramming and genome architecture

Abstract

Funding

RGC Funding Information

Access Output

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Projects

GRF: Dissect Mitochondrial Extracellular Vesicles in Dermatomyositis

TBRS: Single-Cell Multi-Omics Study of Atherosclerotic Vascular Disease: Narrowing the Gap Between Bench and Bedside

GRF: Delineating the Mechanisms of DANCR-Rac1 in Triple-negative Breast Cancer Invasion and Metastasis

Cite this