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Erosion of epigenetic control, resulting in aberrant opening of heterochromatin and de-repression of transposable elements (TEs), is a hallmark feature of aging. We asked if induction of such changes by loss of the TE silencer Daxx in young adult animals also lead to development of aging hallmarks in the hematopoietic system and adult microglia. We found that opening of heterochromatin, by loss of Daxx, is sufficient to cause alterations of cell identity in the hematopoietic system, which results in strong reduction in B cells, increased production of myeloid cells and inflammatory disease, recapitulating hallmarks of inflamm-aging (Gerber*, Russ* et al. Nat Cell Biol 2021). This is driven by dysregulation of the transcription factor Pu.1, including its distribution at enhancers and associated gene promoters.
Single cell transcriptome analysis of microglia after Daxx loss revealed that microglia transition from an interferon-response microglia-like state either toward a state resembling DAM-like microglia, with strong upregulation of Apoe, MHC II genes and proinflammatory genes such as Clec7a or a state resembling homeostatic microglia.
Many neurodegenerative diseases share common pathological responses to abnormal protein production and misfolding in brain cells. This includes overactivation of the unfolded protein response
(UPR), specifically the PERK-eIF2 pathway, resulting in chronic reduction in global protein synthesis rates, leading to synapse and neuronal loss. While alterations in epigenetic regulation and transcription are also observed in prion disease, the dynamics and interplay of epigenetic dysregulation, transcriptional change and UPR activation are not well understood. Pharmacological inhibition of the PERK-eIF2ɑ UPR pathway results in partial restoration of global protein translation rates, rescuing memory, reversing behavioral impairments, preventing neuronal loss, and increasing survival. We are using this to study the potential interplay between translation repression and changes in transcription and the epigenetic landscape in prion disease models. Looking at the dynamics of chromatin perturbations during prion disease progression in CA1 pyramidal neurons suggests that epigenetic changes emerge already at presymptomatic stages, providing a rationale for combinatorial targeting of the epigenome and the UPR.
We highly encourage PhD candidates and postdocs to join the ‘meet the speaker’ session after the talk. Please register by email to cathia.rausch@uni.lu
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