Keywords: hematopoietic stem cells, retroelements, epigenetics, transcriptomics, leukemia Internship Duration: 30/11/-1 - 30/11/-1
Head of the hosting team: Françoise PORTEU
Address of the host laboratory: INSERM U1287 Team Team 1 Hematopoietic Tissue Aging Institut Gustave Roussy, PR1, 114 rue Edouard Vaillant 94805 Villejuif France
Supervisor: Emilie ELVIRA-MATELOTE-mail: emilie.elvira-matelot@inserm.fr Phone: 01 42 11 23 48
Epigenetics is one of the key factors regulating hematopoietic stem cells (HSC) function. Hematopoietic pathologies present a high rate of mutations in epigenetic factors controlling DNA and histone methylation, such as DNMT3A. Loss of function mutations in DNMT3A also arise upon aging where they confer clonal hematopoiesis of indeterminate potential (CHIP). CHIP is characterized by the overproduction of blood cells derived from an HSC harboring somatic mutation(s) that confer a selective clonal advantage. CHIP installs a pre-leukemic state in HSCs and is associated with an increased risk of developing leukemia, cardio-metabolic disease and all-cause mortality. CHIP mutations are most frequently identified in DNMT3A and its prevalence increases with age or inflammation stress. The molecular mechanisms by which these variants confer a fitness advantage to HSCs remain largely unknown. A molecular understanding of CHIP mutations would thus improve our understanding of normal hematopoiesis and help combat this to adverse health conditions in the elderly. The repressive histone mark H3K9me3 plays a crucial role in the maintenance of HSC identity. H3K9me3 controls retrotransposable element (RTEs) expression. Loss of H3K9me3 and increased RTEs are considered as hallmarks of aging. RTEs are major contributors of gene regulatory networks. We previously showed that a strong decrease in H3K9me3 occurs upon stress-induced premature aging in HSCs, and uncovered a link between derepressed RTE and HSC gene deregulation under these conditions (1). Our hypothesis is that DNMT3A loss of function may desorganize HSC heterochromatin, by affecting not only DNA methylation but also the H3K9me3 mark. These alterations, by derepressing RTE, will rewire the transcriptome and act as the driving force behind HSC functional changes and clonal expansion. We are looking for a highly motivated candidate to work on this hypothesis. This project will use a wide range of approaches and techniques including the dissection of WT or Dnmt3amut mice, flow cytometry (cell sorting); molecular biology (RT-qPCR, ChIP-qPCR) ; and whole genome analysis (ATAC-seq, Cut&Tag, RNA-seq).
This project will use a wide range of approaches and techniques including the dissection of WT or Dnmt3amut mice, flow cytometry (cell sorting); molecular biology (RT-qPCR, ChIP-qPCR) ; and whole genome analysis (ATAC-seq, Cut&Tag, RNA-seq).
Pelinski, Y., D. Hidaoui, F. Hermetet, A. Stolz, M.K. Diop, A.M. Chioukh, F. Porteu, and E. Elvira-Matelot. 2021. The NF-κB pathway regulates heterochromatin at intronic young LINE-1 elements and hematopoietic stem cell gene expression during irradiation stress. Cell Biology. https://www.biorxiv.org/content/10.1101/2021.06.08.447574v2
