The role of transposable element-induced inflammation in hematopoietic aging and rejuvenation – heTEro

Aging is one of the major public health challenge. By impacting hematopoietic stem cells (HSCs) function, aging, exposure to irradiation, chemotherapy or chronic inflammation are highly associated with increased risk of developing cancers, and many other aging-related health disorders such as heart or neurocognitive diseases, through decline in the adaptive immunity and enhanced infections and inflammation.

Epigenetic factors are key regulators of HSC function and epigenetic alterations have been observed in aged HSCs. Alteration of heterochromatin in HSCs during age is accompanied by overexpression of transposable elements (TEs) and increased inflammation. TEs are major contributors of gene regulatory networks. They can also be sensed as endogenous genomic parasites, eventually inducing an intrinsic sterile inflammation. Inflammation can in turn induce alterations in heterochromatin and TE expression and worsen the HSC phenotype in a vicious circle.

We hypothesize here that heterochromatin alterations and TEs play a central role in the functional alterations of HSCs and in the production / function of myeloid cells during the aging process.

Through the association of three partners with complementary expertise in epigenetics, transcription, biology, TEs, myelomonocyte differentiation and inflammatory response, we will explore whether:

1/ Alterations in heterochromatin and TE derepression are common events in age and stress
2/ TE derepression, via transcriptome alterations, act as the driving force behind HSC functional changes and their ability to produce monocytes with age
3/ TEs are involved in the inflammatory properties of aged HSCs and monocytes
4/ These pathways can be manipulated by reprogramming to rejuvenate HSC function

This project should identify ways to restore lymphoid/myeloid HSC production and decrease chronic inflammation and immunosenescence by manipulating HSC heterochromatin and TE expression, thereby contributing to healthier aging.