The Gates lab studies the intersection between metabolism, chromatin, and gene regulation. We aim to discover how metabolite signaling to chromatin impacts cell and tissue function in health and disease.
The precise regulation of gene expression is a finely tuned process that is essential for cellular homeostasis, and the misregulation of transcription occurs in disorders and diseases that impact human health, including cancer. The chromatin landscape integrates diverse cellular signals to regulate genome structure and subsequent biological functions, partly through posttranslational modifications (PTMs) on histone proteins. Many donor molecules for histone PTMs are metabolites (e.g., acetyl-CoA is utilized for acetylation), which directly links cellular metabolism to the chromatin landscape. Yet the direct mechanisms and functional significance of the metabolic regulation of chromatin is largely lacking, especially in in vivo settings. We focus on using the mammalian intestine as a model to study the impacts of environmental cues on different aspects of cell biology via metabolism, since the intestine a powerful tissue system in which epithelial cells are subject to diverse environmental stimuli. Here, we study molecular mechanisms that control gene regulation and subsequent cell function in the context of chromatin to answer key questions about gene regulation in health and disease.
Mechanisms of metabolite signaling to chromatin. The chromatin landscape is linked to metabolism, since many donor molecules for histone PTMs are small metabolites. Alterations in the microbiota and diet regulates both the intestinal chromatin landscape and gene expression programs. Now, we aim to understand mechanisms of how these chromatin changes in these physiological contexts relate to specific responses in gene regulation. We aim to trace metabolite signaling to chromatin, investigate how chromatin readers and other proteins interact with histone PTMs, and study the functional role of novel metabolite-derived histone PTMs, including histone butyrylation.
The role of chromatin in intestinal cell fate. The intestinal epithelium is replaced every 3-5 days, providing a unique environment in which epithelial cells must undergo continuous proliferation, migration, and differentiation to specialized cell types. Furthermore, different types of intestinal epithelial cells have distinct metabolic profiles and needs depending on their location in the epithelium and metabolic zones (i.e., crypt vs villi), growth needs, and specialized cell functions. However, the question of how the chromatin landscape changes across cell fates and the functional significance of different chromatin states in intestinal cell identity is largely unknown. We aim to define how chromatin regulates intestinal cell fate, and how specific intestinal cell populations or niches respond to environmental signals.
Metabolism & chromatin in disease. One hallmark of cancers is altered metabolism, which can be exploited for diagnostic and therapeutic uses. Changes in cellular energy needs with transformation and signaling within the local microenvironment can impact cellular metabolism, which in turn can regulate chromatin modifications, partly through the availability of metabolites and the altered activity of chromatin modifying enzymes. In addition, environmental changes (i.e., diet, microbiota) can also regulate tumorigenesis. Now, we are studying how alterations in metabolism change how cells respond to environmental cues and impact tumorigenesis, as well as how cancer-associated mutations in chromatin modifying enzymes alter the intersection between metabolism and chromatin.
Gates LA#, Reis BS, Lund PJ, Paul MR, Leboeuf M, Nadeem Z, Carroll TS, Garcia BA, Mucida D, Allis CD#. “Microbiota-dependent histone butyrylation in the mammalian intestine.” #Co-corresponding authors. BioRxiv [preprint]. September 30, 2022. https://doi.org/10.1101/2022.09.29.510184
- Lund PJ, Gates LA, Leboeuf M, Smith SA, Chau L, Friedman ES, Lopes M, Saiman Y, Kim MS, Petucci, Allis CD, Wu GD, Garcia BA (2022). Stable Isotope Tracing in vivo Reveals A Metabolic Bridge Linking the Microbiota to Host Histone Acetylation. Cell Reports, 41, 111809.
- Williams RT, Guarecuco R, Gates LA, Barrows D, Passarelli MC, Carey B, Baudrier L, Jeewajee S, La K, Prizer B, Malik S, Garcia-Bermudez J, Zhu XG, Cantor J, Molina H, Carroll T, Roeder RG, Abdel-Wahab O, Allis CD, Birsoy K (2020). ZBTB1 Regulates Asparagine Synthesis and Leukemia Cell Response to L-Asparaginase. Cell Metabolism, 31:852-61.
- Wan L, Chong S, Xuan F, Liang A, Cui X, Gates L, Carroll T, Li Y, Feng L, Chen G, Wang S, Ortiz M, Daley S, Wang X, Xuan H, Kentsis A, Muir TW, Roeder RG, Li H, Li W, Tjian R, Wen H#, Allis CD# (2020). Impaired cell fate through gain-of-function mutations in a chromatin reader. Nature, 577:121-126. #Co-corresponding authors.
- Gates LA*, Gu G*, Chen Y, Rohira AD, Lei JT, Hamilton RA, Yu Y, Lonard DM, Wang J, Wang, SP, Edwards DG, Lavere PF, Shao J, Yi P, Jain A, Jung SY, Malovannaya A, Li S, Shao J, Roeder RG, Ellis MJ, Qin J, Fuqua SA, O’Malley BW, Foulds CE (2018). Proteomic profiling identifies key coactivators utilized by mutant ERα proteins as potential new therapeutic targets. Oncogene, 37:4581–4598. *co-first authors.
- Gates LA, Foulds CE, O’Malley BW (2017). Histone marks in the ‘drivers’ seat: functional roles in steering the transcription cycle. Trends in Biochemical Sciences, 42: 977-989.
- Gates LA, Shi J, Rohira A, Feng Q, Zhu B, Bedford MT, Sagum CA, Jung SY, Qin J, Tsai MJ, Tsai SY, Li W, Foulds, CE, O’Malley, BW (2017). Acetylation on histone H3 lysine 9 mediates a switch from transcription initiation to elongation. Journal of Biological Chemistry, 292: 14456-14472.
- Zhu B, Gates LA, Stashi ER, Dasgupta S, Gonzales N, Dean AM, York RB, O’Malley BW (2015). Coactivator-Dependent Oscillation of Chromatin Accessibility Dictates Circadian Gene Amplitude through REV-ERB Loading. Molecular Cell, 60: 769-83.
- Gates LA, Phillips MB, Matter BA, Peterson LA (2014). Comparative metabolism of furan in rodent and human cryopreserved hepatocytes. Drug Metabolism and Disposition, 42: 1132-6.
- Gates LA, Lu D, & Peterson LA (2012). Trapping of cis-2-butene-1,4-dial to measure furan metabolism in human liver microsomes by cytochrome P450 enzymes. Drug Metabolism and Disposition, 40: 596-601.