Gene regulatory elements, networks, and mechanisms

National Institute Of Environmental Health Sciences

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Abstract

Understanding how environmental stimuli influence cellular physiology to produce specific phenotypic outcomes is fundamental to elucidating mechanisms of development and disease. During development and in response to external cues, signaling pathways converge to activate chromatin remodelers and master transcription factors. These effectors work in concert to shape chromatin architecture and establish or maintain gene expression programs that control cell fate decisions. Our laboratory employs integrative, interdisciplinary approaches—merging systems biology, functional genomics, and biochemistry—to map, reconstruct, and characterize gene regulatory networks responsive to developmental and environmental signals. These networks govern essential biological processes, from transcription and signal transduction to cellular adaptation and transformation. A major focus of our research is to understand how dynamic signaling events drive epigenetic and transcriptional programs during development and differentiation, and to apply this knowledge toward developing diagnostic and therapeutic strategies for cancer and other diseases. Bivalent Chromatin and Epigenetic Plasticity. 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 has been 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 mode had not been directly tested. In our recent study (Kumar et al., Genome Research 2021), we challenged this view and demonstrated that bivalent chromatin does not necessarily poise genes for rapid activation. Instead, we showed that it plays a protective role—shielding gene promoters from de novo DNA methylation. Importantly, genes marked bivalent in ESCs and hypermethylated in adult human cancers are strongly associated with a loss of H3K4me3/bivalency in cancer. These findings suggest that bivalency preserves epigenetic plasticity by maintaining genes in a reversibly repressed state, and that loss of bivalency predisposes them to aberrant DNA methylation and irreversible silencing in disease contexts. Our ongoing research is focused on testing this model further. Specifically, we are investigating whether the loss of Mll2—the primary methyltransferase responsible for H3K4me3 at bivalent domains—in mouse ESCs leads to a loss of protection against de novo DNA methylation during the transition from pre- to post-implantation epiblast differentiation. Non-Canonical Role of Crm1 in Chromatin Regulation In earlier work, we predicted an essential role for the nuclear export receptor Crm1 (also known as Exportin1/Xpo1) in regulating ESC identity. While Crm1 is classically known for mediating nuclear export of proteins via NES motifs, our integrative genome-wide, biochemical, and genetic studies have uncovered a novel, non-canonical role for Crm1 on chromatin. We found that Crm1, through its NES-binding groove, associates with chromatin in a MAPK1/ERK2-dependent manner and targets key developmental regulators to facilitate PRC2-mediated gene silencing in mouse ESCs. This chromatin-bound function represents a new layer of epigenetic regulation, linking signaling pathways to transcriptional repression. These findings are currently being compiled into a manuscript for publication. Our ongoing studies aim to elucidate the mechanisms that recruit Crm1 to chromatin and to define its role during early embryonic development. Conclusion Together, our research builds a comprehensive framework for understanding how developmental and environmental signals shape gene regulatory networks. By dissecting the molecular mechanisms that preserve epigenetic plasticity and integrate signaling with transcriptional regulation, we aim to reveal new insights into the control of cell fate and the origins of disease.