The 4D genome in the establishment of adipose cell identity

Project leader:Philippe Collas
Info:Our genome is hierarchically organized in 3 dimensions (3D), laying blueprints of developmental gene expression and cell homeostasis. At a ‘macro’-scale, the genome is organized into chromosome territories, compartments and within those, topologically associating domains or TADs, which conceptually form spatial units of gene regulation. At the nuclear periphery, the nuclear lamina provides radial (center-to-periphery) functionality to the genome. There, A- and B-type lamins interact with chromatin via lamina-associated domains (LADs). LADs are overall heterochromatic and transcriptionally repressive - but not always! We investigate the mechanisms of lamin interactions with chromatin during adipogenic differentiation, the relationship between LADs and TADs as genome organizers, the origin and purpose of LAD heterogeneity, and how LADs contribute to the definition of adipose cell identity. We combine molecular/cell biology, microscopy imaging and genomics approaches to identify how the 3D genome evolves during multilineage stem cell differentiation. We investigate how the nuclear lamina and LADs contribute to the determination of adipose cell fate and cell identity.

Project participants

Julia Madsen Østerbye, Aurélie Bellanger, Natalia Galigniana, Mohamed Abdelhalim, Anita Sørensen; collaborations with Jonas Paulsen, Institute of Biosciences, University of Oslo; Owen Marshall, University of Tasmania, Hobart; David Tremethick, Australian National University, Canberra; Lee H. Wong, Monash University, Melbourne

Ongoing research

Interplay between the nuclear lamina, LADs and TADs in the differentiation of adipose tissue and muscle stem cells
Control of gene expression at the nuclear lamina
Role of lamins on lineage-specific differentiation of adipose stem cells
Nuclear lamins and the epithelial-to-mesenchymal transition
Computational methods for 3D genome modeling

Recent findings

Enhancer-gene connectivity at the nuclear lamina (Madsen-Østerbye 2023 Genes)
'Pockets' of euchromatin and active genes in LADs (Madsen-Østerbye 2022 Genome Biol)
Variable LADs during early adipocyte differentiation are linked to adipose cell identity
A polymer model of chromatin to infer chromatin behavior at the nuclear lamina (Brunet 2021 Nucleus)
TAD cliques shape the 4D genome during adipose differentiation (Paulsen 2019 Nature Genet)
Chrom3D: a platform for 3D genome modeling from Hi-C and LAD data (Paulsen 2017 Genome Biol; Paulsen 2018 Nature Protoc)
Chrom3D on github: https://github.com/Chrom3D/Chrom3D
ChIP protocol for nuclear lamins (Oldenburg 2016 Method Mol Biol)
Manifold-based optimization for 3D modeling of chromatin from sparse Hi-C data (Paulsen 2015 PLoS Comput Biol)
Mechanisms of H3.3 deposition into chromatin (Delbarre 2013 Genome Res; Ivanauskiene 2014 Genome Res); (Delbarre 2017 Genome Res)
Enriched Domain Detector (EDD) to identify LADs and other broad genomic domains (Lund 2014 Nucl Acids Res)
EDD on github: https://github.com/CollasLab/edd