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MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping

Nature Immunology volume 18, pages 10351045 (2017) | Download Citation

Abstract

MLL4 is an essential subunit of the histone H3 Lys4 (H3K4)-methylation complexes. We found that MLL4 deficiency compromised the development of regulatory T cells (Treg cells) and resulted in a substantial decrease in monomethylated H3K4 (H3K4me1) and chromatin interaction at putative gene enhancers, a considerable portion of which were not direct targets of MLL4 but were enhancers that interacted with MLL4-bound sites. The decrease in H3K4me1 and chromatin interaction at the enhancers not bound by MLL4 correlated with MLL4 binding at distant interacting regions. Deletion of an upstream MLL4-binding site diminished the abundance of H3K4me1 at the regulatory elements of the gene encoding the transcription factor Foxp3 that were looped to the MLL4-binding site and compromised both the thymic differentiation and the inducible differentiation of Treg cells. We found that MLL4 catalyzed methylation of H3K4 at distant unbound enhancers via chromatin looping, which identifies a previously unknown mechanism for regulating the T cell enhancer landscape and affecting Treg cell differentiation.

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Acknowledgements

We thank the NHLBI DNA Sequencing Core facility for sequencing the libraries; the NHLBI Systems Biology Core and the NIH Biowulf High Performance Computing Systems for computing services; the NHLBI Flow Cytometry Core facility for cell sorting; the NHLBI and NIAID Animal Facilities for animal care; and X. Wang and S Gao (NHLBI Systems Biology Core) and X. Zheng (Carnegie Institution for Science) for discussions on Hi-C data analysis. Supported by the Division of Intramural Research of NHLBI (K.Z.), NIDCR (W.C.) and NIDDK (K.G.) of the US National Institutes of Health.

Author information

Author notes

    • Katarzyna Placek
    • , Gangqing Hu
    •  & Kairong Cui

    These authors contributed equally to this work.

Affiliations

  1. Systems Biology Center, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland, USA.

    • Katarzyna Placek
    • , Gangqing Hu
    • , Kairong Cui
    • , Yi Ding
    • , Chaochen Wang
    •  & Keji Zhao
  2. Mucosal Immunology Section, Division of Intramural Research, NIDCR, NIH, Bethesda, Maryland, USA.

    • Dunfang Zhang
    • , Joanne Elizabeth Konkel
    •  & Wanjun Chen
  3. Department of Animal and Avian Sciences University of Maryland, College Park, Maryland, USA.

    • Yi Ding
    •  & Jiuzhou Song
  4. Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology and Receptor Biology, NIDDK, NIH, Bethesda, Maryland, USA.

    • Ji-Eun Lee
    • , Younghoon Jang
    • , Chaochen Wang
    •  & Kai Ge
  5. Transgenic Core, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland, USA.

    • Chengyu Liu

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Contributions

K.P., G.H., K.C., C.L., W.C. and K.Z. designed experiments; K.P., G.H., K.C., D.Z., Y.D., J.-E.L., Y.J., C.W., C.L. and K.Z. conducted experiments; K.P., G.H., K.C., D.Z., Y.D., J.-E.L., Y.J., C.W., J.E.K., J.S., C.L., K.G., W.C. and K.Z. analyzed the data; and K.P., G.H., K.C., W.C. and K.Z. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Wanjun Chen or Keji Zhao.

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    Supplementary Text and Figures

    Supplementary Figures 1–8

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    Life Sciences Reporting Summary

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  1. 1.

    Supplementary Table 1

    Expression change of histone modification enzymes associated H3K4me in naive CD4+ T cells upon Mll4 deletion

  2. 2.

    Supplementary Table 2

    Gene ontology enrichment analysis (biological process) on genes down-regulated in expression by Mll4KO in Naïve CD4+ T cells

  3. 3.

    Supplementary Table 3

    Statistics of Hi-C libraries for WT (Mll4 fl/flCd 4Cre-) and KO (Mll4 fl/flCd 4Cre+) cells

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DOI

https://doi.org/10.1038/ni.3812

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