Interplay between SIN3A and STAT3 Mediates Chromatin Conformational Changes and GFAP Expression during Cellular Differentiation

BACKGROUND: Neurons and astrocytes are generated from common neural precursors, yet neurogenesis precedes astrocyte formation during embryogenesis. The mechanisms of neural development underlying suppression and de-suppression of differentiation-related genes for cell fate specifications are not well understood. METHODOLOGY/PRINCIPAL FINDINGS: By using an in vitro system in which NTera-2 cells were induced to differentiate into an astrocyte-like lineage, we revealed a novel role for Sin3A in maintaining the suppression of GFAP in NTera-2 cells. Sin3A coupled with MeCP2 bound to the GFAP promoter and their occupancies were correlated with repression of GFAP transcription. The repression by Sin3A and MeCP2 may be an essential mechanism underlying the inhibition of cell differentiation. Upon commitment toward an astrocyte-like lineage, Sin3A- MeCP2 departed from the promoter and activated STAT3 simultaneously bound to the promoter and exon 1 of GFAP; meanwhile, olig2 was exported from nuclei to the cytoplasm. This suggested that a three-dimensional or higher-order structure was provoked by STAT3 binding between the promoter and proximal coding regions. STAT3 then recruited CBP/p300 to exon 1 and targeted the promoter for histone H3K9 and H3K14 acetylation. The CBP/p300-mediated histone modification further facilitates chromatin remodeling, thereby enhancing H3K4 trimethylation and recruitment of RNA polymerase II to activate GFAP gene transcription. CONCLUSIONS/SIGNIFICANCE: These results provide evidence that exchange of repressor and activator complexes and epigenetic modifications are critical strategies for cellular differentiation and lineage-specific gene expression

STATus and Context within the Mammalian Nervous System

Effective manipulation of human disease processes may be achieved by understanding transcriptional, posttranscriptional and epigenetic events that orchestrate cellular events. The levels of activation of specific molecules, spatial distribution and concentrations of relevant networks of signaling molecules along with the receptiveness of the chromatin to these signals are some of the parameters which dictate context. Effects elicited by the transcription factor signal transducers and activator of transcription 3 (Stat3) are discussed with respect to the context within which Stat3-mediated effects are elicited within the developing and adult mammalian nervous system. Stat3 signals are pivotal to the proliferation and differentiation of neural stem cells. They also participate in neuronal regeneration and cancers of the nervous system. An analysis of the context in which Stat3 activation occurs in these processes provides a potential predictive paradigm with which novel methods for intervention may be designed