A Validated Regulatory Network for Th17 Cell Specification

Abstract

Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively-bound BATF and IRF4 contribute to initial chromatin accessibility, and with STAT3 initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple datasets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease.

STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain

“…It is tempting to speculate that the more condensed conformation in nontransformed MCF-10A cells does not allow STAT3 binding and at the same time prevents transcription of CHOP and other genes through epigenetic mechanisms, whereas open conformation in cancer cells requires STAT3 to suppress CHOP expression. Our observations that STAT3 does not bind the more condensed CHOP promoter (in MCF-10A cells) are also in agreement with a recent report that STAT3 is recruited to already accessible chromatin sites in T-cell receptor-activated CD4 + T cells, but does not pioneer the access itself (38).…”

“…Consequently, other factors are likely to be contributing to selective activation in tumor cells. Taking into consideration the recently published report on STAT3 preferential binding to accessible chromatin (38), it appears likely that different groups of genes are targets for STAT3 binding in nontransformed and malignant cells.…”

The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 + T cells

“…In CD4 + T cells, IRF4 is crucial for the differentiation into T helper (Th) subsets such as Th2, Th9, Th17, and Tfh cells (13)(14)(15)(16)(17)(18). Mechanistically, IRF4 controls B-cell and dendritic cell differentiation by cooperative DNA binding with TFs of the Ets family on Ets-IRF composite elements (EICE) as well as by cooperation with basic leucine zipper transcription factor ATF-like (BATF)-JUN heterodimers in binding to AP-1-IRF4 composite elements (AICE) (19)(20)(21)(22)(23). In contrast, differentiation of CD4 + T cells relies mainly on IRF4 binding to AICE elements (19,21,22).…”

“…Mechanistically, IRF4 controls B-cell and dendritic cell differentiation by cooperative DNA binding with TFs of the Ets family on Ets-IRF composite elements (EICE) as well as by cooperation with basic leucine zipper transcription factor ATF-like (BATF)-JUN heterodimers in binding to AP-1-IRF4 composite elements (AICE) (19)(20)(21)(22)(23). In contrast, differentiation of CD4 + T cells relies mainly on IRF4 binding to AICE elements (19,21,22). Moreover, there is evidence for cooperation of IRF4 with other TFs, including members of the NFAT, STAT, or homeobox protein families (12).…”

Targeting Th17 cells in immune diseases

“…Ciofani et al [4] have recently examined the genes directly bound by RORγ. Interestingly, multiple RORγ-binding sites were identified in the IL-17/IL-17F gene locus.…”