Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells

Polansky, Julia K.; Schreiber, Lisa; Thelemann, Christoph; Ludwig, Leif S.; Krüger, Melanie; Baumgrass, Ria; Cording, Sascha; Floess, Stefan; Hamann, Alf; Huehn, Jochen

doi:10.1007/s00109-010-0642-1

Cited by 185 publications

(159 citation statements)

References 44 publications

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“…S5C). Given that Ets1 and Creb1 bind to their target sites in a demethylation-dependent manner (7,22), the results suggest that some of these transcription factors activate their target genes through direct binding to demethylated TSDRs. (Fig.…”

Section: Resultsmentioning

confidence: 93%

Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation

Morikawa

Ohkura²,

Vandenbon

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

114

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Naturally occurring regulatory T (Treg) cells, which specifically express the transcription factor forkhead box P3 (Foxp3), are engaged in the maintenance of immunological self-tolerance and homeostasis. By transcriptional start site cluster analysis, we assessed here how genome-wide patterns of DNA methylation or Foxp3 binding sites were associated with Treg-specific gene expression. We found that Treg-specific DNA hypomethylated regions were closely associated with Treg up-regulated transcriptional start site clusters, whereas Foxp3 binding regions had no significant correlation with either up- or down-regulated clusters in nonactivated Treg cells. However, in activated Treg cells, Foxp3 binding regions showed a strong correlation with down-regulated clusters. In accordance with these findings, the above two features of activation-dependent gene regulation in Treg cells tend to occur at different locations in the genome. The results collectively indicate that Treg-specific DNA hypomethylation is instrumental in gene up-regulation in steady state Treg cells, whereas Foxp3 down-regulates the expression of its target genes in activated Treg cells. Thus, the two events seem to play distinct but complementary roles in Treg-specific gene expression.

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Section: Resultsmentioning

confidence: 93%

Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation

Morikawa

Ohkura²,

Vandenbon

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

114

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“…There is evidence that the activity of each of these transcription factors is affected by the presence or absence of DNA methylation (3,(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). For some of these transcription factors, the databases contained multiple identical position weight matrices.…”

Section: Methodsmentioning

confidence: 99%

Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus

Suderman

McGowan

Sasaki

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

284

186

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Early life experience is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCOR-TICOID RECEPTOR) gene in the hippocampus of both rats and humans. However, it is unlikely that such effects completely capture the evolutionarily conserved epigenetic mechanisms of early adaptation to environment. Here we present DNA methylation profiles spanning 6.5 million base pairs centered at the NR3C1 gene in the hippocampus of humans who experienced abuse as children and nonabused controls. We compare these profiles to corresponding DNA methylation profiles in rats that received differential levels of maternal care. The profiles of both species reveal hundreds of DNA methylation differences associated with early life experience distributed across the entire region in nonrandom patterns. For instance, methylation differences tend to cluster by genomic location, forming clusters covering as many as 1 million bases. Even more surprisingly, these differences seem to specifically target regulatory regions such as gene promoters, particularly those of the protocadherin α, β, and γ gene families. Beyond these high-level similarities, more detailed analyses reveal methylation differences likely stemming from the significant biological and environmental differences between species. These results provide support for an analogous cross-species epigenetic regulatory response at the level of the genomic region to early life experience.conservation | neuronal plasticity V ariation in early life experience is associated with differences in life-long health and behavioral trajectories in animals as well as humans. For example, differences in maternal care in rats during the first week of life are associated with long-term effects on behavior and brain function that persist into adulthood, including alterations in the stress response (1). In humans, similar effects are observed. For instance, childhood maltreatment associates with development of both externalizing and internalizing personality traits and psychopathology in adulthood (2). The association in both rats and humans of stable developmental phenotypes with early life experience suggests that molecular mechanisms may serve as a memory of these early life experiences in both species. In fact, there is evidence that these long-term effects are, at least in part, mediated by epigenetic alterations in the brain. In particular, recent studies have found aberrant DNA methylation in the NR3C1 (GLUCOCORTICOID RECEPTOR) gene promoter of the hippocampi of both rats and humans associated with differential early life experience (3, 4). Exposure of infant rats to stressed caretakers displaying abusive behavior produced persisting changes in methylation of the BDNF gene promoter in the adult prefrontal cortex (5). Early life stress in mice caused sustained DNA hypomethylation of an important regulatory region of the AVP gene (6).Although explanations involving a single site are appealing, it is unlikely that the broad systemic response to early life experien...

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“…The modifiable mediators of this regulation include methylation,37, 38, 39, 40, 41, 42, 43, 44 acetylation45, 46, 47 and microRNA‐mediated control of transcript translation 28, 48, 49, 50, 51, 52, 53, 54, 55. The global regulation of FOXP3 is influenced by chromatin organises, including SATB1 acts both during development and in mature cells 48, 58.…”

Section: Foxp3 Epigenetic Regulationmentioning

confidence: 99%

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

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Regulatory T cells (Treg) are critical for preventing autoimmunity and curtailing responses of conventional effector T cells (Tconv). The reprogramming of T‐cell fate and function to generate Treg requires switching on and off of key gene regulatory networks, which may be initiated by a subtle shift in expression levels of specific genes. This can be achieved by intermediary regulatory processes that include microRNA and long noncoding RNA‐based regulation of gene expression. There are well‐documented microRNA profiles in Treg and Tconv, and these can operate to either reinforce or reduce expression of a specific set of target genes, including FOXP3 itself. This type of feedforward/feedback regulatory loop is normally stable in the steady state, but can alter in response to local cues or genetic risk. This may go some way to explaining T‐cell plasticity. In addition, in chronic inflammation or autoimmunity, altered Treg/Tconv function may be influenced by changes in enhancer–promoter interactions, which are highly cell type‐specific. These interactions are impacted by genetic risk based on genome‐wide association studies and may cause subtle alterations to the gene regulatory networks controlled by or controlling FOXP3 and its target genes. Recent insights into the 3D organisation of chromatin and the mapping of noncoding regulatory regions to the genes they control are shedding new light on the direct impact of genetic risk on T‐cell function and susceptibility to inflammatory and autoimmune conditions.

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Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells

Cited by 185 publications

References 44 publications

Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation

Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation

Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

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