Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Helmin, Kathryn A.; Morales‐Nebreda, Luisa; Acosta, Manuel A. Torres; Anekalla, Kishore R.; Chen, Shang-Yang; Abdala‐Valencia, Hiam; Politanska, Yuliya; Cheresh, Paul; Akbarpour, Mahzad; Steinert, Elizabeth M.; Weinberg, Samuel E.; Singer, Benjamin D.

doi:10.1172/jci137712

Cited by 64 publications

(78 citation statements)

References 72 publications

(103 reference statements)

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“…Accordingly, Foxp3 complexes with DNMT1 (Wang et al, 2013), though the functional consequences of this interaction remain undefined. A recent study reported that mice with a Treg-specific inducible deletion of the DNMT1 adaptor Uhrf1 resulted in selective CpG demethylation and destabilization of mature mouse Tregs (Helmin et al, 2020). Analogously, we found that FOXP3-induced Treg dysfunction was associated with DNA demethylation in specific regions which were enriched for AP-1 binding sites.…”

Section: Most Of Our Understanding Of the Role Ofsupporting

confidence: 74%

Optimized CRISPR-mediated gene knock-in reveals FOXP3-independent control of human Treg identity

Lam

Lin

Gillies

et al. 2021

Preprint

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SummaryTreg cell therapy is a promising curative approach for a variety of immune-mediated conditions. CRISPR-based genome editing allows precise insertion of transgenes through homology-directed repair, but use in human Tregs has been limited. We report an optimized protocol for CRISPR-mediated gene knock-in in human Tregs with high-yield expansion. To establish a benchmark of human Treg dysfunction, we targeted the master transcription factor FOXP3 in naive and memory Tregs. Although FOXP3-knockout Tregs upregulated cytokine expression, effects on suppressive capacity manifested slowly and primarily in memory Tregs. Moreover, FOXP3-knockout Tregs retained their characteristic phenotype and had few changes in their DNA methylation landscape, with FOXP3 maintaining methylation at regions enriched for AP-1 binding sites. Thus, while FOXP3 is important for human Treg development, it has a limited role in maintaining mature Treg identity. Optimized gene knock-in with human Tregs will enable mechanistic studies and the development of tailored, next-generation Treg cell therapies.

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Section: Most Of Our Understanding Of the Role Ofsupporting

confidence: 74%

Optimized CRISPR-mediated gene knock-in reveals FOXP3-independent control of human Treg identity

Lam

Lin

Gillies

et al. 2021

Preprint

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“…In addition to representing one of the hallmarks of aging, epigenetic phenomena such as DNA methylation regulate the development, differentiation and functional specialization of T cell lineages, including Treg cells (14)(15)(16)30). Therefore, we reasoned that age-related changes to the Treg cell DNA methylome could inform the divergent pro-repair transcriptional response observed between young and aged Treg cells following influenza infection.…”

Section: Dna Methylation Regulates the Transcriptional Pro-repair Resmentioning

confidence: 99%

“…Genomic DNA was isolated from sorted lung Treg cells using Qiagen AllPrep DNA/RNA Micro Kit. Endonuclease digestion, fragment size selection, bisulfite conversion and library preparation were performed as previously described (15,43,(45)(46)(47). Sequencing was performed on a NextSeq 500 instrument (Illumina).…”

Section: Modified Reduced Representation Bisulfite Sequencingmentioning

confidence: 99%

Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia

et al. 2021

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Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury following viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell pro-repair function following lung injury remains unknown. Here, we show that aging results in a cell-autonomous impairment of reparative Treg cell function following experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provide insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Novel strategies that restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia.

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“…Previous studies have shown that the epigenetic factor UHRF1 regulates transcription by modulating DNA methylation and histone modification, and plays critical roles in proliferation, development, and tumorigenesis. Recently, some reports indicated that UHRF1 regulates the proliferation, survival, and differentiation of Treg cells and iNKT cells [33][34][35][36][37]. However, whether UHRF1 is involved in regulating the differentiation of Tfh cells and its role in the pathogenesis of SLE still remain unclear.…”

Section: Discussionmentioning

confidence: 99%

UHRF1 downregulation promotes T follicular helper cell differentiation by increasing BCL6 expression in SLE

Liu

Yang

et al. 2021

Clin Epigenet

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Background Transcription factor B cell lymphoma 6 (BCL6) is a master regulator of T follicular helper (Tfh) cells, which play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanisms by which BCL6 expression is regulated are poorly understood. Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an important epigenetic factor that regulates DNA methylation and histone modifications. In the present study, we assessed whether UHRF1 can regulate BCL6 expression and influence the differentiation and proliferation of Tfh cells. Results Compared to healthy controls, the mean fluorescence intensity of UHRF1 (UHRF1-MFI) in Tfh cells from SLE patients was significantly downregulated, whereas that of BCL6 (BCL6-MFI) was significantly upregulated. In vitro, UHRF1 knockdown led to BCL6 overexpression and promoted Tfh cell differentiation. In contrast, UHRF1 overexpression led to BCL6 downregulation and decreased Tfh cell differentiation. In vivo, conditional UHRF1 gene knockout (UHRF1-cKO) in mouse T cells revealed that UHRF1 depletion can enhance the proportion of Tfh cells and induce an augmented GC reaction in mice treated with NP-keyhole limpet hemocyanin (NP-KLH). Mechanistically, UHRF1 downregulation can decrease DNA methylation and H3K27 trimethylation (H3K27me3) levels in the BCL6 promoter region of Tfh cells. Conclusions Our results demonstrated that UHRF1 downregulation leads to increased BCL6 expression by decreasing DNA methylation and H3K27me3 levels, promoting Tfh cell differentiation in vitro and in vivo. This finding reveals the role of UHRF1 in regulating Tfh cell differentiation and provides a potential target for SLE therapy.

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Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

Cited by 64 publications

References 72 publications

Optimized CRISPR-mediated gene knock-in reveals FOXP3-independent control of human Treg identity

Optimized CRISPR-mediated gene knock-in reveals FOXP3-independent control of human Treg identity

Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia

UHRF1 downregulation promotes T follicular helper cell differentiation by increasing BCL6 expression in SLE

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