Epigenetic and Transcriptional Functions of Nuclear Receptors and Chromatin Remodeling Proteins in Stem and Cancer Cells

National Institute Of Environmental Health Sciences

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Abstract

The elegant organization of nucleic acids, predominantly DNA, into chromatin serves essential structural and regulatory roles in eukaryotic cells. This beautiful architecture allows for an expansion of the underlying genetic information by overlaying a spectrum of epigenetic controls. The interplay between genome accessibility, chromatin posttranslational modifications and transcriptional activity is a critical hub of gene expression regulation. Fundamental to many disease processes is a dysregulation of transcription that underlies the critical role regulated gene transcription plays in normal development physiology and homeostasis. A major focus, of the Archer group has been an understanding of how epigenetic enzymes, including chromatin remodeling proteins such as the SWI/SNF complex, work with transcription factors, such as the glucocorticoid receptor, to respond to environmental cues, both internal and external. Many of our studies have utilize the glucocorticoid receptor, a ligand-activated transcription factor that has important functions in many aspects of mammalian physiology including development, reproduction, immune response, cardiac function, and energy metabolism. Consistent with the broad physiological functions, dysregulation of GR activity is a major factor in health and disease. In this way we hope to understand the function of both the receptor and the requirement for chromatin remodeling and other epigenetic enzymes in these processes. The advent of both embryonic stem cells as well as induced pluripotency stem cells (iPSCs) have opened a significant avenue of experimental approaches to understand both normal and disease states in humans. Many of the studies with pluripotent stem cells have affirmed a major determinant of a role for epigenetics as a mechanism by which the DNA residing in all cells can have specific features of pluripotency. We generated and compared transcriptomic data from dermal fibroblast-iPSC pairs with consistent variation in reprogramming efficiency. Using samples from self-reported African Americans and European Americans, we identified both ancestry-dependent and ancestry-independent transcripts associated with reprogramming efficiency, suggesting that transcriptomic heterogeneity can substantially affect reprogramming. Research pursued in the chromatin and gene expression group aligns with the NIEHS strategic plan and multiple goals within its six major themes particularly with respect to basic biological research, outreach communications and engagement, environmental health disparities, the professional pipeline, and training in capacity building in global health framework. Together these studies allow us to fulfill the mission of the NIEHS to improve an understanding of environmental impact on human health and development. Our very recent work has focused on improving our understanding of fundamental issues of chromatin and epigenetics in environmental context. The convergence of epigenetic factors that allow regulated gene expression in a varied and changing environment represents a critical question in biology. Nucleosomes at actively transcribed promoters have specific histone post-transcriptional modifications and histone variants. These features are thought to contribute to the formation and maintenance of a permissive chromatin environment. Recent reports have drawn conflicting conclusions about whether these histone modifications depend on transcription. We used triptolide to inhibit transcription initiation and degrade RNA Polymerase II and interrogated the effect on histone modifications. Transcription initiation was dispensable for de novo and steady-state histone acetylation at transcription start sites (TSSs) and enhancers. However, at steady state, blocking transcription initiation increased the levels of histone acetylation and H2AZ incorporation at active TSSs. These results demonstrate that deposition of specific histone modifications at TSSs is not dependent on transcription and that transcription limits the maintenance of these marks. (Hoffman JA et al., Sci Adv 2025) To more fully understand the underlying mechanisms by which epigenetics informs our responses to the environment we need a better understanding of the underlying structure of the genome. Nucleosomes are flanked by histone H1’s which bind linker DNA and aid chromatin compaction. The specific role of linker histone has remained elusive due to complex compensatory mechanisms among H1 variants. H1.4 ablation resulted in robust changes in nascent transcription and gene expression, with critical pathways upregulated (RAR, TNF-α/NF-κB) and extracellular matrix and collagen genes repressed. Alternations to chromatin accessibility intersected extragenic and intronic regions, overlapped sites of known enhancer chromatin, and were of enhancer-size. These sites exhibited concomitant and concordant changes to epigenetic marks (H3K27ac/H3K4me1). Sites which gained accessibility contained binding motifs for basal factors (TBP, SRF), localized to polycomb, heterochromatin and quiescent/low chromatin and gained active RNA transcription in ΔH1.4 cells. However, the AP-1 motif was enriched at sites which lost accessibility, consistent with the gene expression changes. This places histone H1.4 as a hitherto underappreciated regulator of transcriptional response patterns and a dynamic member of regulatory chromatin. (Gokey et al., in press).