MLL4 prepares the enhancer landscape for  Foxp3  induction via chromatin looping

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Abstract

MLL4 is an essential subunit of the H3K4 methylation complexes. We report that MLL4 deficiency compromised regulatory T (T _reg) cell development and resulted in substantial decreases in H3K4me1 and chromatin interaction at putative enhancers, a remarkable portion of which were not direct targets of MLL4 but were enhancers that interact with MLL4-bound sites. The decrease in H3K4me1 and chromatin interaction at the MLL4-unbound enhancers correlated with MLL4 binding at distant-interacting regions. Deletion of an upstream MLL4 binding site reduced H3K4me1 at the Foxp3 regulatory elements looped to the MLL4 binding site and compromised both thymic T _reg and inducible T _reg cell differentiation. We show that MLL4 catalyzed H3K4 methylation at distant unbound enhancers via chromatin looping, thus providing a new mechanism of regulating T cell enhancer landscape and impacting T _reg cell differentiation.

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A clustering approach for identification of enriched domains from histone modification ChIP-Seq data.

Chongzhi Zang, Dustin E. Schones, Chen Zeng … (2009)

Chromatin states are the key to gene regulation and cell identity. Chromatin immunoprecipitation (ChIP) coupled with high-throughput sequencing (ChIP-Seq) is increasingly being used to map epigenetic states across genomes of diverse species. Chromatin modification profiles are frequently noisy and diffuse, spanning regions ranging from several nucleosomes to large domains of multiple genes. Much of the early work on the identification of ChIP-enriched regions for ChIP-Seq data has focused on identifying localized regions, such as transcription factor binding sites. Bioinformatic tools to identify diffuse domains of ChIP-enriched regions have been lacking. Based on the biological observation that histone modifications tend to cluster to form domains, we present a method that identifies spatial clusters of signals unlikely to appear by chance. This method pools together enrichment information from neighboring nucleosomes to increase sensitivity and specificity. By using genomic-scale analysis, as well as the examination of loci with validated epigenetic states, we demonstrate that this method outperforms existing methods in the identification of ChIP-enriched signals for histone modification profiles. We demonstrate the application of this unbiased method in important issues in ChIP-Seq data analysis, such as data normalization for quantitative comparison of levels of epigenetic modifications across cell types and growth conditions. http://home.gwu.edu/ approximately wpeng/Software.htm. Supplementary data are available at Bioinformatics online.

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A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival.

Peggy Lee, David FitzPatrick, Caroline Beard … (2001)

The role of DNA methylation and of the maintenance DNA methyltransferase Dnmt1 in the epigenetic regulation of developmental stage- and cell lineage-specific gene expression in vivo is uncertain. This is addressed here through the generation of mice in which Dnmt1 was inactivated by Cre/loxP-mediated deletion at sequential stages of T cell development. Deletion of Dnmt1 in early double-negative thymocytes led to impaired survival of TCRalphabeta(+) cells and the generation of atypical CD8(+)TCRgammadelta(+) cells. Deletion of Dnmt1 in double-positive thymocytes impaired activation-induced proliferation but differentially enhanced cytokine mRNA expression by naive peripheral T cells. We conclude that Dnmt1 and DNA methylation are required for the proper expression of certain genes that define fate and determine function in T cells.

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Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease

Katharina Lahl, Christoph Loddenkemper, Cathy Drouin … (2007)

The scurfy mutant mouse strain suffers from a fatal lymphoproliferative disease leading to early death within 3–4 wk of age. A frame-shift mutation of the forkhead box transcription factor Foxp3 has been identified as the molecular cause of this multiorgan autoimmune disease. Foxp3 is a central control element in the development and function of regulatory T cells (T reg cells), which are necessary for the maintenance of self-tolerance. However, it is unclear whether dysfunction or a lack of T reg cells is etiologically involved in scurfy pathogenesis and its human correlate, the IPEX syndrome. We describe the generation of bacterial artificial chromosome–transgenic mice termed “depletion of regulatory T cell” (DEREG) mice expressing a diphtheria toxin (DT) receptor–enhanced green fluorescent protein fusion protein under the control of the foxp3 gene locus, allowing selective and efficient depletion of Foxp3+ T reg cells by DT injection. Ablation of Foxp3+ T reg cells in newborn DEREG mice led to the development of scurfy-like symptoms with splenomegaly, lymphadenopathy, insulitis, and severe skin inflammation. Thus, these data provide experimental evidence that the absence of Foxp3+ T reg cells is indeed sufficient to induce a scurfy-like phenotype. Furthermore, DEREG mice will allow a more precise definition of the function of Foxp3+ T reg cells in immune reactions in vivo.

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Author and article information

Journal

Journal ID (nlm-journal-id): 100941354

Journal ID (pubmed-jr-id): 21750

Journal ID (nlm-ta): Nat Immunol

Journal ID (iso-abbrev): Nat. Immunol.

Title: Nature immunology

ISSN (Print): 1529-2908

ISSN (Electronic): 1529-2916

Publication date Nihms-submitted: 27 February 2018

Publication date (Electronic): 31 July 2017

Publication date (Print): September 2017

Publication date PMC-release: 05 March 2018

Volume: 18

Issue: 9

Pages: 1035-1045

Affiliations

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

[2 ]Mucosal Immunology Section, Division of Intramural Research, NIDCR, NIH, Bethesda, Maryland, USA

[3 ]Department of Animal and Avian Sciences University of Maryland, College Park MD 20742-2311 USA

[4 ]Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology and Receptor Biology, NIDDK, NIH, Bethesda, Maryland, USA

[5 ]Transgenic Core, Division of Intramural Research, NHLBI, NIH, Bethesda, Maryland, USA

Author notes

Correspondence should be addressed to W.C. ( wchen@ 123456dir.nidcr.nih.gov ) or K.Z. ( zhaok@ 123456nhlbi.nih.gov )

[6]

These authors contributed equally to this work.

Article

Manuscript ID: NIHMS891919

DOI: 10.1038/ni.3812

PMC ID: 5836551

PubMed ID: 28759003

SO-VID: 24abe897-ba7c-4139-ae22-d8902fecae9c

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MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping

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Regulatory T cell (Treg) therapy

Most cited references 22

A clustering approach for identification of enriched domains from histone modification ChIP-Seq data.

A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival.

Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease

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