The di Luccio lab: Epigenetics at atomic details
Research interests
- • Epigenetics, chromatin dynamics
- • Targeting epigenetic enzymes for drug discovery
- • Epigenetic of human infertility
- • Epigenetic memory
Keywords
- ◦ Molecular and cellular biology
- ◦ Enzymology and biochemistry
- ◦ Yeast cell biology
- ◦ Structural biology
- ◦ Drug-design
The di Luccio research group has an avid interest in understanding chromatin dynamics at atomic details and the dramatic changes seen in diseases, especially cancers. The di Luccio research group is interested in understanding epigenetic memory on histones and its implications in human pathologies as well as the role of epigenetic in human infertility.
Research in the di Luccio research group is translational from basic science to drug development, at the interface between biochemistry, molecular and cell biology, pharmacology, structural biology (X-ray crystallography, Small-angle X-ray scattering SAXS) and computational biology.
Human and Yeast histone methyltransferases
Histones are the stage of diverse post-translational modifications that ultimately regulates the gene transcription. Covalent histone modifications such as histone modification, lysine methylation, can have both activating and repressive functions on transcriptional events. Histone lysine methyltransferases (HMTases) are transcriptional co-regulators that target specific lysines on histone H3 and H4, and can transfer up to three methyl groups (Kme1, Kme2, and Kme3). Dysfunctions in the regulation of histone methylation are linked to an increasing number of pathological conditions including oncogenesis and tumor progression.
Our laboratory focuses on understanding the biology of human and yeast histone methyltransferases, from a cell biology approach to structure-based drug-design.
Structure-function studies on oncogenic NSD2/MMSET Histone methyl transferase.
Set7 from S. pombe is a H3K37 methyltransferase and required for proper gametogenesis: implication in men spermatogenesis infertility
We first discovered, characterized, and solved the crystal structure of Schizosaccharomyces pombe Set7, an HMTase methylating the uncharted histone H3 lysine 37 (H3K37) mark. Set7 forms a dimer with its substrate-binding site structurally specific to K37, not the neighboring well-studied K36 mark. We also discovered that H3K37 methylation levels dramatically increase during gametogenesis. Set7 deletion mutant cells show defects in gametogenesis and produce the abnormal number of spores with aberrant morphology. S. pombe gametogenesis shares similarities with mammalian spermatogenesis. These findings extend our understanding of epigenetic regulation during gametogenesis and support a link between Set7, the epigenetic H3K37 methyl mark, and proper gametogenesis.
Identification of in vitro Set7 substrates by MALDI-TOF mass spectrometry: histone H3.1 incubated with (red spectra) or without (black spectra) Set7 was treated with trypsin and analyzed by MALDI-TOF. Peaks indicating H3K37me1, -me2, and -me3 were detected, but none for H3K36 and H4K20me marks.
(Left) Set7-GFP cellular localization: Set7-GFP localizes in both the nucleus and the cytoplasm in an asynchronous culture expressing Set7-GFP under the thiamine- repressive nmt41 promoter.
(Right) Illustration of S. pombe gametogenesis: upon nitrogen starvation, S. pombe homothallic h90 cells containing both two mating-type, h+ and h-, initiate mating to form a diploid zygote which then produces four mature spores through meiosis and sporulation.
Targeting epigenetic enzymes for drug discovery
Our laboratory is designing specific and selective HMTase inhibitors targeting the NSD family (NSD1, NSD2/MMSET/WHSC1 and NSD3/WHSC1L1). Using X-ray crystallography, Small-angle X-ray scattering SAXS and computational analysis (virtual ligand screening), we search, design, and optimize small molecules and small peptides that could potentially be of pharmacological interest for further drug developments.
Structure-based drug design on oncogenic NSD2/MMSET Histone methyl transferase.
© Eric di luccio - Kyungpook National University