Poster Presentation 46th Lorne Genome Conference 2025

SET-9 and SET-26 impact transgenerational epigenetic inheritance and germline mortality through their PHD finger and SET domains (#211)

Dhruv Monteiro 1 , Biswaranjan Mohanty 1 , Natasha Jones 2 , J Ni 3 , Walter Becker 1 , Sam Gu 3 , Joel Mackay 1 , Alyson Ashe 1
  1. School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia
  2. Monash University, Melbourne, VIC, Australia
  3. Department of Molecular Biology and Biochemistry, Rutgers, the State University of New Jersey, Piscataway, NJ, Unites States of America

Transgenerational epigenetic inheritance (TEI), the transmission of epigenetic states between generations, has been observed in complex organisms ranging from plants to nematode worms, insects and mammals. Studies of TEI in Caenorhabditis elegans have shown that TEI involves both nuclear and cytoplasmic components, while most genes involved in the process are involved in small RNA pathways. While the role of these pathways has been well established, to date only two histone methyltransferases have been implicated in TEI, set-25 and set-32, and so the importance of chromatin regulation in TEI is less clear. Here, we demonstrate that two more chromatin-related genes, set-9 and set-26, are also required for TEI. In addition, we identify a third gene that lacks any predicted ordered domains; we name this gene intrinsically disordered protein-1 (idp-1). Strikingly, idp-1 also has a role in TEI. set-9 and set-26 each contain a PHD finger and a SET domain. A combination of structural and functional assays shows that both domains are critical for TEI, despite the likely absence of histone lysine methyltransferase activity in the SET domains. In contrast to previous studies, we show that the PHD fingers bind trimethylated histone 3 lysine 4 (H3K4me3) in the absence of adjacent histone marks. These findings solidify the importance of chromatin-related proteins and showcase the importance of intrinsically disordered proteins in TEI.