Figure 8.

The role of Egr2 in the transcriptional cascade mediating IL4/STAT6-induced alternative polarization. The Th2-type cytokine IL-4 induces the phenotypic switch of macrophages to become alternatively polarized (top). The immediate early transcriptional regulator of alternative polarization STAT6 orchestrates a rapidly developing but transient gene expression program including the marker genes of polarization (Mrc1 and Arg1). The transcription factor EGR2 is also subject to IL-4/STAT6-mediated early induction via enhancer activation (H3K27ac) and RNAPII recruitment (middle panel). Once the polarization program proceeds to the late stages, EGR2 becomes a central component by guiding the transition between early and late polarization, acting as a “molecular linchpin” via forming an extensive cistrome and chromatin remodeling activity. EGR2 regulates the vast majority of the late polarization program including the signature genes of this stage (Retnla, Ccl17, and Itgax). Moreover, EGR2 controls the expression of an entire transcription factor cascade including PPARG, BHLHE40, and KLF4 with important roles in alternative macrophage polarization. This program is sustained partly by EGR2's autoregulatory activity.