My long term goal is to comprehensively understand the diversity, heterogeneity and functions of bacterial epigenomes both in terms of basic science and biomedical impact. In the bacterial world, methylated adenine and cytosine residues was previously thought to be only associated with restriction-modification systems that provide a defense mechanism against invading foreign genomes. However, increasing evidence supports that they also play important roles in the regulation of cell cycle, gene expression, virulence, sporulation, biofilm formation, microbe-host interaction and antibiotic resistance. Efficient and high resolution profiling of bacterial DNA methylation events has not been possible until the advent of Single Molecule Real-Time (SMRT) sequencing. This technique enabled us to characterize the first bacterial methylome at single nucleotide resolution. A fast growing number of bacteria are being characterized, from which exciting discoveries have been made. However, these studies have also revealed unexpected complexity and diversity in bacterial methylomes, calling for the development new technologies, analytical and experimental methods in order to more comprehensively understand bacterial epigenomes. In this R35 project, we will build on the progress we have made in the past five years to further develop an integrated research program with a broader scope integrating two ongoing focused R01 projects. The overarching theme is focused on the mapping, characterization and exploitation of bacterial methylomes to better understand individual bacteria and microbiome community. We will develop this research program along four complementary themes. First, to more comprehensively map bacterial methylome, we will continue to innovate on technology development to make significant improvements both in terms of in terms of completeness and resolution. Second, to better elucidate epigenetic regulation in bacteria, we will combine computational and experimental approaches to prioritize and functionally characterize specific methylation events across different bacterial organisms. Third, to systematically expand bacterial methylome research from cultured individual bacteria to microbiome, we will characterize bacterial epigenetics in response to different types of perturbations. Last, we will provide the software we develop as an integrated package to ease broad usage, and organize relevant conference tutorials to help the broader community. Combined together, we expect this project to provide broadly applicable methods to the microbiology and microbiome community, and discover novel biological insights into epigenetic regulation in individual bacteria and microbiome.

Public Health Relevance

Many bacteria are causal pathogens for infectious diseases with strong abilities to develop drug resistance, bypass immune system and adapt to different host environments, while other commensal bacteria play important roles at the interface of host metabolism and the immune system. We aim to develop methods that enable the multiscale mapping, functional characterization and exploitation of bacterial DNA methylation towards the discovery of novel mechanisms in individual bacteria and the mammalian gut microbiome.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1)
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Gindhart, Joseph G
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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