ChroMet - Coupling metabolic state to spatial chromatin organization in adipose progenitor cells
Determination of stem cell fate has been long ascribed to signaling pathways affecting gene regulation, and as a result shifting cell identity to self-renewal or differentiation. Recently, cellular metabolism has emerged as a key determinant of stem cell function, adding a new layer of complexity to understanding stem cell fate. Given recent evidence linking nutrient availability and chromatin modifications, we will examine the nature of a dynamic relationship between metabolic state and chromatin organization in adipose stem cells (ASCs).
Our preliminary data show, during adipogenic differentiation of human ASCs, a dynamic interaction of nuclear lamins (in particular lamin A; LMNA) with chromatin regions enriched in in O-linked beta-N-acetylglucosamine modification of histone H2B (H2B-S112GlcNAc). As H2BGlcNAc is seen as a nutrient sensor, we aim to test the main hypothesis that cellular metabolic status modulates spatial genome organization through H2B GlcNAcylation and developmentally regulated association with nuclear lamins. We will test two hypotheses. The first is that domains of H2BGlcNAc predict LMNA-genome interactions during adipogenesis. This will be tested by replacing H2B by a non-S112-GlcNAcylabe H2BS112A mutant and assessing impact on LMNA-chromatin interactions during adipogenic differentiation. The second is that H2BGlcNAc-LMNA interactions mediate the impact of metabolic insults on genome organization. After evaluating global effects of altering glucose metabolism on protein GlcNAcylation, we will assess the remodeling of genomic distribution of H2BGlcNAc and LMNA as a result of these metabolic changes, and the function of H2BGlcNAc and LMNA redistribution on adipogenic differentiation. The project combines adipose stem cell biology, metabolic studies, chromatin biology and high-throughput genomics, and is designed for a PhD student.
- Begrunnelse: Ikke sensitive data
- Lagret: Room 2268
- Ansvarlig: Philippe Collas
REK - Ja 2 filer
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Tidspunkt for anonymisering og sletting av dataene
- Anonymisering: desember 2013
- Sletting: desember 2023