Oral Presentation 39th Annual Lorne Genome Conference 2018

Loss of Suv39h1 and h2 histone methyltransferases results in disruption of chromatin organisation which leads to immune progeria (#46)

Christine R Keenan 1 2 , Nadia Iannarella 1 , Hannah D Coughlan 1 2 , Alexandra L Garnham 1 2 , Gordon K Smyth 1 3 , Rhys S Allan 1 2
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  3. School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, Australia

Epigenetic changes are considered a hallmark of aging. However, the molecular drivers for these changes are not well described. Suv39h1 and Suv39h2 enzymes are responsible for trimethylating lysine 9 of histone 3 (H3K9me3) leading to stable gene silencing through the formation of heterochromatin via recruitment of heterochromatin 1 proteins. Suv39h1 expression decreases with age, and Suv39h2, whilst ubiquitously expressed during embryogenesis, is expressed at low levels in all adult tissues except the testes.

Deletion of Suv39h repressive enzymes would be expected to cause aberrant gene activation. However, remarkably, RNASeq on double-positive thymocytes, precursors of both CD4+ and CD8+ T lymphocytes, from mice deficient in both Suv39h enzymes (Suv39dn) showed widespread gene repression. These Suv39dn cells also show disordered heterochromatin and a marked loss of LaminB1 protein leading to altered nuclear morphology. Interestingly, in contrast to the majority of differentially-expressed genes, LaminB1-chromatin immunoprecipitation (ChIP) of wildtype thymocytes reveals that the majority of lamina-interacting genes are significantly up-regulated suggesting that disruption of nuclear lamina-tethering leads to selective gene activation for this subset of genes.

Together with molecular changes, aging leads to well-characterised changes in adaptive immunity resulting in reduced immune function and an increased frequency of infections among older individuals. These changes include reduced haematopoietic stem cell (HSC) potential, reduced CD8+ lymphocyte numbers, and an increased frequency of spontaneous antigen-naïve memory cells. Importantly, these age-associated immune features are recapitulated in Suv39dn where we see reduced HSC potential revealed through poor reconstitution of bone-marrow chimeras by Suv39dn cells. Furthermore, reduced CD8+ T lymphocyte numbers and increased memory CD8+ T cells were observed.

Taken together, these results suggest that decreased levels of Suv39h1 and h2 in aging drives a loss of heterochromatin and nuclear lamina integrity which in turn drives the loss of immune function and susceptibility of older individuals to infections.