The Interplay between Transcription Factors and Epigenetic Modifications in Th2 Cells

Abstract

Functionally polarized CD4 T helper (Th) cells, such as Th1, Th2, and Th17 cells, are essential for the regulation of acquired immunity. Diferentiation of naïve CD4 T cells into Th2 cells is characterized by chromatin remodeling and the induced expression of a set of Th2-speciic genes, which include Th2 cytokine genes. In the irst stage of this differentiation, a Th2-skewing cytokine environment, especially IL-4, induces STAT6 activation. Activated STAT6 increases the expression of GATA3, a master regulator of Th2 cell diferentiation, via direct binding to the Gata3 gene locus. This transcriptional induction of Gata3 mRNA during Th2 cell diferentiation is accompanied by dynamic changes in the binding paterns of two epigenetic modiication proteins such as Polycomb and Trithorax complexes. Consequently, expressed GATA3 epigenetically modiies and upregulates Th2-speciic genes to establish Th2 cell identity. This identity is maintained by high-level expression of the Gata3 gene controlled by Menin, which is a member of the Trithorax proteins, after cycles of cultivation in vitro and a long-term resting state in vivo. Thus, the Menin-GATA3 axis handles the Th2-speciic gene regulatory network.

Epigenetic and Transcriptional Regulation in the Induction, Maintenance, Heterogeneity, and Recall-Response of Effector and Memory Th2 Cells

“…It has been reported that several cis-regulatory elements (also known as locus control regions) at Th2 cytokine gene loci are also bound by GATA3. These regulatory elements include the conserved GATA response element (CGRE), the conserved non-coding sequence (CNS)-1, CNS-2, hypersensitive site HSVa, and HSII within the Il4 gene (52–56). CGRE, which was originally identified in 2002 as a region containing four consensus GATA-binding sequences, overlaps with the previously identified HSI.…”

“…Interestingly, the CGRE forms a boundary between hyper- and hypo-acetylated regions. This fact implies that GATA3 primarily binds to the CGRE and secondarily spreads histone hyperacetylation toward the 3′-end of the Il13 gene (52). Indeed, the association of GATA3 with histone acetyltransferases CBP, p300, and RNA polymerase II is observed in this region (57, 59).…”

“…In fact, the decreased expression of Il5 and Il13 was observed in differentiated effector Th2 cells in which the Gata3 gene was knocked down by siRNA just before TCR restimulation. Furthermore, other Th2 signature genes are transcriptionally regulated by GATA3 in effector Th2 cells (52). The expression of approximately half of the Th2-specific genes (16 out of 31) in effector Th2 cells was significantly reduced by Gata3 siRNA knockdown; the Tube1 gene was the only gene for which the expression was significantly increased, indicating that one of the major roles of GATA3 is the transcriptional activation of target genes (52, 58).…”

“…These signatures are maintained by the high-level expression of GATA3 in an IL-4-independent manner (14, 59, 73–75). In addition, the expression of Th2 cytokine genes in memory Th2 cells depends on GATA3, since Gata3 knockdown diminishes the transcription of these and other Th2-specific genes (52, 58). When TrxG proteins are genetically depleted, memory Th2 cells fail to maintain the Gata3 expression and produce reduced amounts of Th2 cytokines after TCR stimulation due to the decreased methylation of H3K4 and the acetylation of H3K9.…”

RUNX1 gene expression changes in the placentas of women smokers

“…This finding is consistent with the observed increase in IL-4 RNA expression and decrease in T-BET expression, and reflects a possible imbalance in the response of CD4 TLs. Transcriptional activation of GATA3 may be associated with the presence of histone covalent modifications associated with activation, which are associated with an epigenetic mechanism underlying the transcriptional modulation of the allergic response ( 37 , 38 ). For the protein expression of GATA3 detected by immunohistochemistry, the results did not show significant changes between the groups analyzed.…”