Project 1: Structural basis for epigenetics in aging and longevity

Project leader

Ronen Marmorstein, PhD.
Wistar Institute

Description

The overall goal of Project 1 is to use the human histone chaperone HIRA and the yeast post-translational modification enzyme, Sir2, as models to understand the structural basis for epigenetic control in aging and longevity; and to develop small molecule Sir2 effectors as reagents to study the linkage between epigenetic events and cell aging.

HIRA forms a complex with the proteins ASF1a, UBN1/2 and CABIN 1 to mediate DNA replication-independent chromatin assembly during processes such as transcriptional activation and formation of senescent heterochromatin, a process associated with tissue aging.  In previous collaborative studies with Dr. Adams (Project 4), we uncovered the molecular basis for ASF1a recognition of HIRA that occurs mutually exclusively with ASF1a recognition of CAF-1, a histone complex that is associated with DNA-replication dependent chromatin assembly.  We are currently extending our studies with other members of the program to further characterize the biochemical and structural basis for how HIRA mediates replication-independent chromatin assembly.

The yeast Sir2 protein, and its orthologs in higher eukaryotes (called sirtuins), is an NAD+ dependent histone deacetylase.  Yeast Sir2 promotes gene silencing and lifespan extension and its SIRT1 human ortholog has been implicated to counteract age-associated diseases such as type-II diabetes, obesity and neurodegenerative disorders in mammals.  In previous studies, we have determined crystal structures of the yeast Sir2 protein, Hst2, in various liganded forms to derive information about substrate recognition and the catalytic mechanism of sirtuins.  We also collaborated with Dr. Berger (Project 2) to identify and characterize new small molecule inhibitor scaffolds for Sir2.   We are currently collaborating with other members of the program to continue to identify and further develop small molecule sirtuin effectors and to probe the unique biochemical functions of the different mammalian sirtuin proteins.

Our largely chemical, structural and biochemical studies are greatly complemented by the largely genetic, cell biology and organismal studies on the HIRA and sirtuin proteins that are carried out by other projects of the program, and the protein production capability of Core B.  Together, these studies contribute to the general understanding of the link between epigenetics and aging and may lead to the development of small molecule compounds to treat age-associated disorders.

Key Personnel

  • Emily Chen Ding
  • Elise Hoi
  • Min Pan
  • Yong Tang
  • Hua Yuan
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