Nuclear enzymes, chromatin and its modifications mediate the responses of cells and organisms to dynamic environments. Chromatin remodeling influences gene expression by providing transcription factors and the transcription machinery with dynamic access to an otherwise tightly packaged genome. Many chromatin-modifying enzymes require metabolites as cofactors; therefore, the cell metabolic state can influence chromatin structure and epigenetic processes. However, little is known about how metabolic states and chromatin regulation are coordinated to allow cells and organisms to respond to environmental conditions. We are using Arabidopsis to study the metabolic states and chromatin regulation in ethylene signaling. Our group pioneered the study of histone regulation in ethylene signaling. The ethylene signal is perceived on the endoplasmic reticulum (ER) membrane, and the cleavage and nuclear translocation of EIN2 mediates the signal from the ER membrane to the nucleus. The EIN2 C-terminus (EIN2-C) is cleaved and translocated to the nucleus to initiate the ethylene response. During the last funding period, we discovered that EIN2, an essential signaling factor, is also a key component of the histone modification that directly regulates H3K14Ac and H3K23Ac to mediate the transcriptional response to ethylene. EIN2 is thus the direct link between ethylene signaling and chromatin regulation. We also identified a noncanonical histone acetyltransferase (HAT) domain-containing protein EHAT that directly interacts with the EIN2-C in the nucleus. Our preliminary data strongly suggest that EHAT links EIN2-mediated ethylene signaling with EIN2-meidated regulation of histone acetylation. Strikingly, our new data provide solid evidence that the pyruvate dehydrogenase complex, which converts pyruvate to acetyl-CoA, the acetyl-donor of histone acetylation, interacts with EIN2-C and that the subunits of the complex can translocate from the mitochondria to the nucleus in response to ethylene. This new discovery provides a strong rational for the hypothesis that acetyl-CoA biosynthesis is involved in the EIN2-mediated interplay between chromatin regulation and ethylene signaling. In this proposal, we will study metabolic states and chromatin regulation in ethylene signaling by focusing on the following specific aims: (1) elucidate the detailed mechanisms governing EIN2-dependent histone modification in response to ethylene; (2) investigate the function of the metabolic enzyme pyruvate dehydrogenase in EIN2- mediated chromatin and transcriptional regulation in response to ethylene, and (3) elucidate the molecular mechanisms by which the EIN2-C is translocated to the nucleus in response to ethylene. Our work will have broad implications as dysfunctions of nuclear processes contribute directly to cancer progression and genetic disorders and imbalances between metabolism and chromatin activities can trigger severe metabolic disease.
The coordinate metabolic states and chromatin regulation allow cells and organisms to respond to dynamic environments. We are using Arabidopsis to study the metabolic states and chromatin regulation in ethylene signaling, which will allow us to gain a deep understanding of how nuclear dysfunctions and imbalances between metabolism and chromatin activities contribute directly to disease processes. Our long-term goal is to develop a validated mechanistic model that accurately describes the molecular mechanism of the integration of metabolic state and histone modification in hormone signaling.
