Assistant Professor of Medicinal Chemistry
Chromatin and Histone Modifications, Epigenetics and Metabolism, Protein Chemistry, Metabolite Sensors
The eukaryotic genome is regulated by a variety of epigenetic mechanisms that establish and maintain proper gene expression profiles to control cell identity and fate. One of these vital mechanisms is accomplished by chromatin, which is the packaging medium for genomic DNA. The chromatin polymer consists of individual nucleosomes in which the DNA is wrapped around an octamer of the canonical histone proteins H2A, H2B, H3, and H4. The histone proteins are highly post-translationally modified, and these modifications (PTMs) have an impact on the local chromatin environment through both direct biophysical perturbations and recruitment of downstream effectors. Different PTM chemotypes (e.g., methylation, acetylation, ADP-ribosylation) at different sites within the histones act as dynamic signals to delineate specific chromatin states. Thus, far from being a passive scaffold for the genome, chromatin actively controls access to the underlying genetic material to aid in regulating transcription, translation, and repair. Importantly, when histone PTMs and other epigenetic factors are disrupted, these processes are misregulated leading to diseases such as cancer and developmental disorders.
Our lab studies how the deposition, removal, and recognition of these histone PTMs are regulated and what downstream effects these PTMs have on DNA-mediated processes. In particular, our focus is studying how metabolism is linked to genomic regulation via the metabolites that fuel chromatin dynamics. We seek to elucidate mechanisms by which the metabolic state of the cell (e.g., acetyl-CoA level) is reported to the genome via chromatin (e.g., histone acetylation) to lead to changes in DNA transcription, translation, or repair. To do so, my lab will utilize a range of techniques across organic chemistry, peptide/protein chemistry, biochemistry, and molecular and cell biology.
Some project areas include 1) biochemical and in cell characterization of mechanisms by which the histone deacetylases called sirtuins sense and report on cellular metabolism, 2) development of fluorescent sensors for metabolites and histone post-translational modifications (PTMs) for obtaining detailed metabolite/PTM profiles in live cells, 3) investigation of NAD+ and ATP dynamics during the DNA damage response, and 4) characterization of mechanisms for the subnuclear localization of metabolic enzymes and development of strategies to target this localization.
References (Selected Publications)
- Diehl KL, Muir TW (2020). Chromatin as a key consumer in the metabolite economy. Nat Chem Biol, 16(6), 620-629.
- Diehl, KL, Ge, EJ, Weinberg, DN, Jani, KS, Allis, CD, Muir, TW (2019). PRC2 engages a bivalent H3K27M-H3K27me3 dinucleosome inhibitor. Proc Natl Acad Sci U S A, 116(44), 22152-22157.
- Ge EJ, Jani KS, Diehl KL, Müller MM, Muir TW (2019). Nucleation and Propagation of Heterochromatin by the Histone Methyltransferase PRC2: Geometric Constraints and Impact of the Regulatory Subunit JARID2. J Am Chem Soc, 141(38), 15029-15039.
- Liszczak G,* Diehl KL,* Dann GP, Muir TW (2018). Acetylation blocks DNA damage–induced chromatin ADP-ribosylation. Nat Chem Biol, 14(9), 837–840. *authors contributed equally
- Dann GP, Liszczak GP, Bagert JD, Müller MM, Nguyen UTT, Wojcik F, Brown ZZ, Bos J, Panchenko T, Pihl R, Pollock SB, Diehl KL, Allis CD, Muir TW (2017). ISWI chromatin remodellers sense nucleosome modifications to determine substrate preference. Nature, 548(7669), 607-611.
- Diehl KL, Bachman JL, Anslyn EV (2017). Tuning thiol addition to squaraines by ortho-substitution and the use of serum albumin. Dyes and Pigments, 141, 316-324.
- Diehl KL, Kolesnichenko IV, Robotham SA, Bachman JL, Zhong Y, Brodbelt JS, Anslyn EV (2016). Click and chemically triggered declick reactions through reversible amine and thiol coupling via a conjugate acceptor. Nat Chem, 8, 968-973.
- Diehl KL, Ivy MA, Rabidoux S, Petry SM, Müller G, Anslyn EV (2015). Differential sensing for the regio- and stereoselective identification and quantitation of glycerides. Proc Natl Acad Sci U S A, 112(30), E3977-86.