Köhne, Maren Christin: The chromatin organizer Satb1 regulates the differentiation into CD4+ TH subsets and is essential for the development of TH17 cells. - Bonn, 2021. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-62543
@phdthesis{handle:20.500.11811/9123,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-62543,
author = {{Maren Christin Köhne}},
title = {The chromatin organizer Satb1 regulates the differentiation into CD4+ TH subsets and is essential for the development of TH17 cells},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2021,
month = jun,

note = {CD4+ T cells play a critical role in host defense and tissue homeostasis. Upon encountering their specific antigen, naive CD4+ T cells can differentiate into the effector T helper (TH) subsets TH1, TH2, TH9, TH17 and regulatory T cells (Treg), which fulfill various functions. T cell dysfunction is associated with increased susceptibility to pathogen infections, autoimmune diseases as well as cancer formation. Therefore, it is critical to identify the common underlying mechanisms governing T cell differentiation and to establish new approaches to influence their differentiation in disease settings. Special AT-rich sequence-binding protein 1 (Satb1) is a nuclear matrix protein regulating gene expression by organizing the chromatin structure and recruiting chromatin modifying factors to their target gene loci. Thereby, Satb1 plays an important role in the development of T cells. However, its role in TH subsets has not been studied in detail.
In this thesis, analysis of the impact of Satb1 on TH cell differentiation in vitro revealed that Satb1 is a critical player in the naive CD4+ T cell differentiation process. Expression of Satb1 is important for the differentiation of TH9 and TH17 cells, while its downregulation accelerates the differentiation of TH1 and iTreg cells. In addition, aberrant Satb1 expression diminishes the generation of TH2 cells.
Especially the differentiation of TH17 cells is affected by the loss of Satb1 in vitro, an observation which was also mirrored in vivo both during homeostasis and in TH17 cell-driven disease settings. In both the experimental autoimmune encephalomyelitis (EAE) and the adoptive transfer colitis model, mice are protected from disease development when Satb1 is deleted in CD4+ T cells due to diminished development of TH17 cells.
Further analysis revealed that Satb1 is important during the early stages of TH17 cell development by orchestrating expression of the TH17 cell gene network. In addition, Satb1 expression improves TH17 cell function upon restimulation and is required for reprogramming TH1 cells into TH17 cells.
Characterization of the transcriptional program and chromatin accessibility of Satb1-deficient naive CD4+ T cells indicated an altered activation state already in naive CD4+ T cells. One dysregulated gene locus in Satb1-deficient naive CD4+ T cells is Il2. Satb1 is essential for inhibiting IL-2 expression by preventing access to the genomic Il2 locus and thus preventing pre-activation of naive CD4+ T cells.
During the early steps of TH17 cell development, loss of Satb1 results in increased IL-2 signaling indicated by the phosphorylation of Stat5, an upregulation of CD25 as well as a reduction in the expression of the IL-6 receptor. Strikingly, blocking IL-2 signaling in Satb1-deficient CD4+ T cells restores TH17 cell development, indicating that Satb1 regulates the generation of TH17 cells through inhibiting IL-2 signaling.
Taken together, Satb1 is an important pioneer factor in TH cell differentiation. Satb1 is critical for the differentiation of TH17 cells through epigenetic programming of naive CD4+ T cells as well as through chromatin organization during the early stages of TH17 cell development by preventing accessibility of the genomic Il2 locus. Thus, Satb1 might be a promising novel therapeutic target for the treatment of TH17-cell driven autoimmune diseases.},

url = {https://hdl.handle.net/20.500.11811/9123}
}

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