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JMJD2 regulates enhancer–promoter interactions via biomolecular condensate formation

Nature Genetics (2025)Cite this article

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Abstract

Enhancer–promoter (E-P) interactions regulate transcription during cell fate determination. However, the regulatory mechanisms underlying E-P interactions have remained elusive. Here we present a chromatin-interaction-based proteomic approach, LoopID, to profile proteins (termed the looposome) at certain E-P anchors. We find that histone demethylase JMJD2, a key looposome component, can regulate E-P interactions and the looposome in a catalytic-independent manner through formation of biomolecular condensates. Furthermore, we introduce a system to engineer E-P interactions by assembling JMJD2 condensates at certain genomic loci, enabling construction of cell-type-specific E-P interactions to promote cellular reprogramming into pluripotent or two-cell-like cells. Our findings reveal a noncanonical function of a histone demethylase in regulation of chromatin organization and provide a strategy to regulate cell fate transitions through E-P interactions.

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Fig. 1: Establishment of LoopID to identify looposome proteins.
Fig. 2: Histone demethylase JMJD2 maintains E-P interactions and looposome.
Fig. 3: JMJD2 maintains E-P interactions by forming biomolecular condensates.
Fig. 4: JMJD2 maintains the looposome by forming biomolecular condensates.
Fig. 5: JMJD2 condensates can maintain pluripotent E-P interactions in ES cells in a catalytic-independent manner.
Fig. 6: JMJD2 condensates can promote two-cell specific E-P interactions after overexpression in a catalytic-independent manner.
Fig. 7: Engineering two-cell-specific E-P interactions and enhancing ES cell-to-2CLC transition via JMJD2 condensate assembly at certain genomic loci.

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Data availability

All omics data generated in this study are summarized in Supplementary Table 8. HiChIP (mES cell H3K27ac), AQuA-HiChIP (H3K27ac), Micro-C (mES cell), 4C–seq (mES cell E-P loop of Zscan4c), ChIP–seq and Cut&Tag (mES cell H3K27ac, H3K36me3, H3K4me3, H3K9me2, H3K9me3, JMJD2A, JMJD2C, SadCas9, SpdCas9, YY1) are available through the Gene Expression Omnibus under accession GSE232848. The proteomics data generated in this study have been deposited in PRIDE under accession number PXD069064. Public ChIP–seq data from mES cells: BRD4 (Sabari et al.7, GSE112808); CBX2, EZH2 and RING1B (Deaton et al.56, GSE78899); CTCF, H3K27ac, H3K4me1 and H3K4me3 (Shen et al.50, GSE29218); H3K27ac and p300 (Chronis et al.57, GSE90893); H3K9me3 (Cho et al.58, GSE106176); HDAC1, HDAC2 and LSD1 (Whyte et al.59, GSE27841); HP1 and SMYD5 (Kidder et al.60, GSE94033); JARID1B (Schmitz et al.61, GSE31966); Jmjd2a/b/c-TKO (long-term) H3K9me3 (Pedersen et al.22, GSE64254); JMJD2B and JMJD2C (Das et al.36, GSE43231); JMJD3 (Banaszynski et al.62, GSE42152); MLL2 and SUZ12 (Mas et al.63, GSE99530); MLL3/4 (Dorighi et al.64, GSE98063); MLL4 (Cao et al.65, GSE99022); OCT4 (Whyte et al.66, GSE44286); PRDM4 (Bogani et al.67, GSE48372); SET1A (Sze et al.68, GSE98988); SETDB1 (Bilodeau et al.69, GSE18371); SUV39H1 and SUV39H2 (Bulut-Karslioglu et al.70, GSE57092); TET1 (Williams et al.71, GSE24841); YY1 (Weintraub et al.9, GSE99518); USF1 and WDR5 (Scelfo et al.72, GSE122715); UTX (Wang et al.73, GSE103180). Public ChIP–seq data from two-cell embryos: H3K27ac and H3K4me3 (Dahl et al.74, GSE72784). Public ChIP–seq data from 2CLCs: H3K27ac and H3K4me3 (Zhu et al.46, GSE159623). Public 3D genome data from mES cells: H3K27ac HiChIP (Mumbach et al.14, GSE101498); from two-cell embryos: Hi-C (Du et al.75, GSE82185); from 2CLCs: Hi-C (Zhu et al.46, GSE159623). Public RNA-seq data from from 2CLCs (Zhu et al.46, GSE159623), ciTotiSCs (Hu et al.76, GSE185000); mES cells, D-EPSCs and L-EPSCs (Posfai et al.77, GSE145609); two-cell embryos (Zhang et al.78, GSE71434); TLSCs (Yang et al.54, GSE166204); bulk RNA-seq of mouse embryos (Wu et al.79, GSE66390); and single-cell RNA-seq from mouse embryos (Fan et al.80, GSE53386), totipotent blastomere-like cells (Shen et al.81, GSE168728) and totipotent-like stem cells (Xu et al.82, GSE183522). Source data are provided with this paper.

Code availability

Software and algorithms used in this study were as follows: scripts written in-house for this study (Calculation of maintaining score, https://github.com/XinyiLiu671/LoopID), 10X Genomics Cell Ranger v.7.1.0 (Zheng et al.83, https://www.10xgenomics.com), Basic4Cseq v.1.38.0 (Walter et al.84, https://bioconductor.org/packages/release/bioc/html/Basic4Cseq.html), bedtools v.2.26.0 (Quinlan et al.85, https://github.com/arq5x/bedtools), BioGPS (Wu et al.86, http://biogps.org/#goto=welcome), Bowtie2 v.2.3.0 (Langmead et al.87, https://github.com/arq5x/bedtools), Cas-OFFinder (Bae et al.88, http://www.rgenome.net/cas-offinder/), CRISPick (https://portals.broadinstitute.org/gppx/crispick/public), crisprScore v.1.10.0, (Hoberecht et al.89, https://www.bioconductor.org/packages/release/bioc/html/crisprScore.html), Cytoscape v.3.9.1 (Shannon et al.90, https://cytoscape.org), DAVID (Sherman et al.55, https://david.ncifcrf.gov/tools.jsp), DeepTools v.3.5.1 (Ramírez et al.91, https://deeptools.readthedocs.io/en/develop/content/list_of_tools.html), diffloop v.1.14.0 (Lareau et al.92, http://bioconductor.org/packages/release/bioc/html/diffloop.html), EdgeR v.3.26.5 (Robinson et al.93, https://bioconductor.org/packages/release/bioc/html/edgeR.html), Fastp v.0.23.2 (Chen et al.94, https://github.com/OpenGene/fastp), FourCSeq v.1.2.0 (Klein et al.95, https://bioconductor.riken.jp/packages/3.1/bioc/html/FourCSeq.html), GENOVA v.0.95 (van der Weide et al.96, https://github.com/robinweide/GENOVA), ggplot2 v.3.4.3 (Wickham97, https://ggplot2.tidyverse.org), ggpubr v.0.6.0 (Kassambara98, https://cran.r-project.org/web/packages/ggpubr/index.html), GSEA v.4.0.3 (Subramanian et al.99, https://www.gsea-msigdb.org/gsea/index.jsp), HiCExplore v.3.7.1 (Wolff et al.100, https://hicexplorer.readthedocs.io/en/latest/index.html), hichipper v.0.7.5 (Lareau et al.101, https://github.com/aryeelab/hichipper), HiC-Pro v.2.10.0 (Servant et al.102, https://github.com/nservant/HiC-Pro), HOMER v.4.11 (Heinz et al.103, http://homer.ucsd.edu/homer), HTSeq-count v.0.11.2 (Anders et al.104, https://github.com/simon-anders/htseq), IGV v.2.4.10 (Thorvaldsdottir et al.105, http://software.broadinstitute.org/software/igv), ImageJ (Schneider et al.106, https://imagej.nih.gov), Imaris (Bitplane, https://imaris.oxinst.com), Juicebox v.1.9.8 (Robinson et al.107, https://www.aidenlab.org/juicebox), Macs2 v.2.1.2 (Zhang et al.108, https://github.com/taoliu/MACS), Mouse Reference Genome, NCBI build 37, NCBI37/mm9 (Genome Reference Consortium, https://www.ncbi.nlm.nih.gov/grc/mouse), PANTHER (Thomas et al.109, https://www.pantherdb.org), Perl v.5.34.0 (Wall et al.110, https://www.perl.org), SAINTexpress v.3.3 (Teo et al.17, https://saint-apms.sourceforge.net/Main.html).

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Acknowledgements

We thank K. Helin and K. Agger (University of Copenhagen, Denmark) for help with JMJD2 cell lines, and R. A. Young (Whitehead Institute for Biomedical Research, USA) for pET-mEGFP plasmids. This work was funded by the National Key Research and Development Program of China (2023YFA1800900) (J.J.D.); National Key Research and Development Program of China (2024YFA1106900) (J.J.D.); National Science Foundation for Distinguished Young Scholars of China (32425022) (J.J.D.); National Natural Science Foundation of China (32170798 and 32430031) (J.J.D.); Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S029) (J.J.D.); National Natural Science Foundation of China (32300669) (S.S.J.); Sun Yat-sen University Fundamental Research Funds for Colleges and Universities Young Teachers Cultivation Project (23ptpy89) (S.S.J.); Natural Science Foundation of Guangdong Province (2024A1515011174) (S.S.J.); National Natural Science Foundation of China (32400659) (X.Y.L.); China Postdoctoral Science Foundation (2023M744082) (X.Y.L.); Natural Science Foundation of Guangdong Province (2023A1515010148) (J.S.); National Natural Science Foundation of China (32400561) (J.S.); Guangdong Basic and Applied Basic Research Foundation (2025B1515020011) (L.L.F.); Guangzhou Science and Technology Program Project, China (No.2025A04J5154) (L.L.F.); National Natural Science Foundation of China (82304746) (L.L.F.); National Natural Science Foundation of China (323B2026) (J.L.Q.); and NIH/NHGRI (1R35HG010717-01) (L.P.); Rappaport MGH Research Scholar Award 2024-2029 (L.P.).

Author information

Author notes

  1. These authors contributed equally: Shaoshuai Jiang, Xinyi Liu, Zhuheng Zhang, Mingzhu Yang.

Authors and Affiliations

  1. Department of Rehabilitation Medicine, The Seventh Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangdong, China

    Shaoshuai Jiang, Xinyi Liu, Zhuheng Zhang, Mingzhu Yang, Xing Zhu, Lin Ma, Longying Zhao, Xiaoru Ling, Ziqiang Zhou, Ziqiang Wu, Jiale Qu, Haochen Li, Qi Tian, Xiaona Huang, Xianglin Huang, Jin Tan, Jun Sun, Dong-feng Huang, Jichang Wang, Hancheng Lin & Junjun Ding

  2. Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Jiangsu, China; School of Basic Medical Sciences, Guangdong Medical University, Guangdong, China

    Shaoshuai Jiang, Xinyi Liu, Zhuheng Zhang, Hongfu Wu, Jin Bai & Junjun Ding

  3. Frontiers Medical Center, Tianfu Jincheng Laboratory; Department of Gynecology and Obstetrics, West China Second Hospital; West China Biomedical Big Data Center, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China

    Shaoshuai Jiang, Xinyi Liu, Zhuheng Zhang, Jun Sun, Xue Xiao & Junjun Ding

  4. Shenzhen Eye Hospital, Shenzhen Eye Medical Center, Southern Medical University, Shenzhen, China

    Shaoshuai Jiang, Xinyi Liu, Zhuheng Zhang, Wei Chi & Junjun Ding

  5. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

    Mingzhu Yang

  6. Department of Chemistry, Tsinghua-Peking Joint Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, China

    Ziqiang Zhou, Jiawei Liang & Zhiheng Deng

  7. GMU-GIBH Joint School of Life Sciences, Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, China

    Jia Wang

  8. Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), Universidade de Santiago de Compostela (USC)-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain

    Diana Guallar

  9. Department of Anatomy and Developmental Biology, Monash University, Wellington Road, Clayton, Victoria, Australia

    Partha Pratim Das

  10. Molecular Pathology Unit, Center for Cancer Research, Massachusetts General Hospital, Department of Pathology, Harvard Medical School, Boston, MA, USA; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Luca Pinello

  11. Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, China

    Liang Wang

  12. Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Jinan University, Guangzhou, China

    Lili Fan

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Contributions

S.J., X.L. and J.D. designed the study; S.J., X.L. and J.D. discussed the results and wrote the manuscript with input from all other authors; X.L. performed bioinformatic analyses and visualizations; X.H., J.T., Z. Zhang. and L.M. conducted experiments on biomolecular condensates; X.Z., X.L., H. Lin., X.H. and Z. Zhang performed the LoopID, HiChIP and ChIP experiments; Q.T., Z.W., Z. Zhou, L.Z., H. Li. and J.Q. constructed plasmids and performed transfections; P.P.D. and L.P. provided the ChIP–seq data for JMJD2A and KDM4A; J.L. and Z.D. prepared nucleosome arrays modified with H3K4me3; M.Y. generated the chimeras; and J.S., J.W., H.W., D.-f.H., J.B., L.F., W.C., X.X., J.C.W., D.G. and L.W. provided guidance for the manuscript.

Corresponding authors

Correspondence to Jin Bai, Lili Fan, Wei Chi, Xue Xiao or Junjun Ding.

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Nature Genetics thanks Alessio Zippo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Jiang, S., Liu, X., Zhang, Z. et al. JMJD2 regulates enhancer–promoter interactions via biomolecular condensate formation. Nat Genet (2025). https://doi.org/10.1038/s41588-025-02415-8

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