Gene regulatory elements, networks, and mechanisms

National Institute Of Environmental Health Sciences

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Abstract

Understanding how an environmental stimulant affects cellular physiology to give rise to a specific phenotypic outcome is a fundamental step toward understanding development and pathogenesis. During development and in response to environmental insults, various signaling cascades culminate in the activation of key chromatin remodeling enzymes and transcription factors, which collectively modulate the chromatin architecture to establish and/or maintain gene expression programs controlling cell identity. Our laboratory uses integrative interdisciplinary approaches merging systems biology, functional genomics, and biochemistry to map, reconstruct, and characterize developmentally- and environmentally-responsive gene networks that control fundamental biological processes ranging from transcription and signal transduction to cellular response to changes in the environment. Specifically, we seek to understand how transcription regulators and epigenetic modifications regulate gene expression programs controling cell fate decisions during cellular development and differentiation. Bivalent chromatin is characterized by the simultaneous presence of H3K4me3 and H3K27me3, histone modifications generally associated with transcriptionally active and repressed chromatin, respectively. Prevalent in embryonic stem cells (ESCs), bivalency is postulated to poise/prime lineage-controlling developmental genes for rapid activation during embryogenesis while maintaining a transcriptionally repressed state in the absence of activation cues; however, this hypothesis remains to be directly tested. Most gene promoters DNA-hypermethylated in adult human cancers are bivalently marked in ESCs, and it was speculated that bivalency predisposes them for aberrant de novo DNA methylation and irreversible silencing in cancer, but evidence supporting this model is largely lacking. We showed that bivalent chromatin does not poise genes for rapid activation but protects promoters from de novo DNA methylation. Genome-wide studies in differentiating ESCs revealed that activation of bivalent genes is no more rapid than that of other transcriptionally silent genes, challenging the premise that H3K4me3 is instructive for transcription. Notably, H3K4me3 at bivalent promotersa product of the underlying DNA sequencepersists in nearly all cell types irrespective of gene expression and confers protection from de novo DNA methylation. Bivalent genes in ESCs that are frequent targets of aberrant hypermethylation in cancer are particularly strongly associated with loss of H3K4me3/bivalency in cancer. Altogether, our findings suggest that bivalency protects reversibly repressed genes from irreversible silencing and that loss of bivalency may make them more susceptible to aberrant DNA methylation in diseases such as cancer. Bivalency may thus represent a distinct regulatory mechanism for maintaining epigenetic plasticity. Collectively, our studies provide a foundation for defining the mechanism and scope of developmentally- and environmentally- responsive gene networks.