The epigenome, a term referring to the state of DNA methylation and histone modifications, plays a central role in regulating the functional output of the genome in response to environmental signals. Changes in the epigenome can determine future patterns of gene regulation, allowing cells to adapt cellular responses over time. Such adaptation is important during ?-cell development, when differentiation cues need to be read in a context-specific manner. Similarly, during adulthood, ?-cells need to adapt insulin secretion to lasting changes in the nutrient environment. How ?-cells and their precursors read environmental signals and translate these signals into context-specific responses is poorly understood. Preliminary unpublished evidence from our laboratory suggests that by modifying the epigenome, the histone demethylase LSD1 plays an important role in determining future cellular responses to environmental signals in the context of both ?-cell development and mature ?-cells. We have found that during ?-cell development, LSD1 removes activating epigenetic marks from early pancreatic enhancers, thereby limiting the duration during which retinoic acid (RA) can activate early pancreatic genes. Furthermore, we have obtained evidence that in ?-cells, LSD1 modifies the epigenetic state of enhancers linked to ?-cell metabolism genes, thereby modulating future insulin secretory responses. We hypothesize that LSD1 functions as an integration hub between the cell's environment and transcriptional output, and by regulating the epigenome, LSD1 determines how ?-cells and their precursors respond to environmental stimuli. To determine the mechanisms by which LSD1 regulates ?-cell differentiation during development and insulin secretion in mature ?-cells, we will employ state-of-the-art approaches, encompassing novel mouse models, a human embryonic stem cell (hESC)-based in vitro differentiation system of ?-cells, human islet experiments, genome-wide profiling of chromatin state and gene expression, and cutting-edge computational analysis.
In Aim 1, we will determine how LSD1 controls ?-cell differentiation. To accomplish this, we will manipulate LSD1 activity and RA exposure in a hESC-based ?-cell differentiation system, and investigate the link between RA signaling, LSD1, chromatin, and ?-cell differentiation.
In Aim 2, we will assess the role of LSD1 in adapting ?-cell insulin secretion to nutrient deprivation using mouse genetic models and human islets. Here, we will manipulate LSD1 activity and the nutrient environment and study how these manipulations affect insulin secretory responses, chromatin state, and ?-cell gene transcription. Finally, in Aim 3, we will exam ?-cell chromatin state in overnutrition models to determine the role of LSD1 in adaptation of ?-cells to chronically increased workload. By unveiling fundamental mechanisms by which environmental signals adapt cellular responses through modification of the epigenome, this proposal will prove critical for developing ?-cell programming strategies and for understanding how ?-cells respond to metabolic challenges, as in obesity and type 2 diabetes.

Public Health Relevance

Adapting gene expression to environmental signals is important during ?-cell development, when ?-cell precursors need to respond to differentiation cues, as well as during adulthood, when ?-cells need to adapt their gene expression profiles to changes in the nutrient environment. How ?-cells and their precursors read environmental signals and translate these signals into transcriptional responses is poorly understood. Here, we will determine the mechanisms by which the nutrient-sensitive histone demethylase, LSD1, regulates embryonic ?-cell differentiation and insulin secretion in mature ?-cells.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Sato, Sheryl M
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University of California, San Diego
Schools of Medicine
La Jolla
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