Grimaud, C. | bioRxiv Science

bioRxiv2024

Temporal and spatial niche partitioning in a retrotransposon community of the Drosophila genome

Transposable elements (TEs), widespread genetic parasites, pose potential threats to the stability of their host genomes. Hence, the interactions observed today between TEs and their host genomes, as well as among the different TE species coexisting in the same host, likely reflect those that did not lead to the extinction of either the host or the TEs. It is not clear to what extent the expression and integration steps of the TE replication cycles are involved in this peaceful coexistence. Here, we show that four Drosophila LTR RetroTransposable Elements (LTR-RTEs), although sharing the same overall integration mechanism, preferentially integrate into distinct open chromatin domains of the host germline. Notably, the differential expressions of the gtwin and ZAM LTR-RTEs in ovarian and embryonic somatic tissues, respectively, result in differential integration timings and targeting of accessible chromatin landscapes that differ between early and late embryonic nuclei, highlighting connections between temporal and spatial LTR-RTEs niche partitionings.

genomics↗

bioRxiv2019

Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma

Multiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable. The search for new therapeutic targets is therefore essential. Here we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for histone H4K20 mono-methylation, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Remarkably, primary malignant plasma cells are particularly addicted to SETD8 activity. Indeed, pharmacological inhibition of this enzyme by the chemical compound UNC0379 demonstrated a significantly higher toxicity in MM cells compared to normal cells from the bone marrow microenvironment. Moreover, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and an activation of the p53 canonical pathway, which together leads to an impairment of myeloma cell proliferation and survival. However, UNC0379 treatment triggers a deadly level of replicative stress in p53 deficient MM cells, indicating that the cytotoxicity associated with SETD8 inhibition is independent of the p53 status. Consistent with this, the combination of UNC0379 with the conventional cytotoxic agent melphalan strongly enhances DNA damage and overcomes drug resistance in myeloma cells. Thus, targeting SETD8 could be of therapeutic interest to improve MM treatment in high-risk patients independently of the p53 status.

cancer biology↗