Project description:Age-related skeletal muscle atrophy or sarcopenia is a significant societal problem that is becoming amplified as the world’s population continues to increase. A critical contributor to sarcopenia is the loss in the number and function of muscle stem cells, which maintain tissue homeostasis and regenerate damage. The molecular mechanisms that govern muscle stem cell aging encompass changes across multiple regulatory layers and are integrated by the three-dimensional organization of the genome. To quantitatively understand how hierarchical chromatin architecture changes during muscle stem cell aging, we generated 3D chromatin conformation maps (Hi-C) and integrated these datasets with multi-omic (chromatin accessibility and transcriptome) profiles from bulk populations and single cells. We observed that muscle stem cells display static behavior at global scales of chromatin organization during aging and extensive rewiring of local contacts at finer scales that were associated with variations in transcription factor binding and aberrant gene expression. These data provide insights into genome topology as a regulator of molecular function in stem cell aging.
Project description:Age-related skeletal muscle atrophy or sarcopenia is a significant societal problem that is becoming amplified as the world’s population continues to increase. A critical contributor to sarcopenia is the loss in the number and function of muscle stem cells, which maintain tissue homeostasis and regenerate damage. The molecular mechanisms that govern muscle stem cell aging encompass changes across multiple regulatory layers and are integrated by the three-dimensional organization of the genome. To quantitatively understand how hierarchical chromatin architecture changes during muscle stem cell aging, we generated 3D chromatin conformation maps (Hi-C) and integrated these datasets with multi-omic (chromatin accessibility and transcriptome) profiles from bulk populations and single cells. We observed that muscle stem cells display static behavior at global scales of chromatin organization during aging and extensive rewiring of local contacts at finer scales that were associated with variations in transcription factor binding and aberrant gene expression. These data provide insights into genome topology as a regulator of molecular function in stem cell aging.
Project description:Age-related skeletal muscle atrophy or sarcopenia is a significant societal problem that is becoming amplified as the world’s population continues to increase. A critical contributor to sarcopenia is the loss in the number and function of muscle stem cells, which maintain tissue homeostasis and regenerate damage. The molecular mechanisms that govern muscle stem cell aging encompass changes across multiple regulatory layers and are integrated by the three-dimensional organization of the genome. To quantitatively understand how hierarchical chromatin architecture changes during muscle stem cell aging, we generated 3D chromatin conformation maps (Hi-C) and integrated these datasets with multi-omic (chromatin accessibility and transcriptome) profiles from bulk populations and single cells. We observed that muscle stem cells display static behavior at global scales of chromatin organization during aging and extensive rewiring of local contacts at finer scales that were associated with variations in transcription factor binding and aberrant gene expression. These data provide insights into genome topology as a regulator of molecular function in stem cell aging.
Project description:Three-dimensional (3D) organization of the genome is essential for precise patterns of gene expression required for biological processes, however its role in physiological aging is not known.Here we show that large scale chromatin re-organization distinguishes bone marrow progenitor (pro-) B cells of old mice from that of young mice.These changes result in increased interactions at the compartment level and reduced interactions within topologically associated domains (TADs).One genomic region that transitions from compartment A to B with age contains the gene encoding Ebf1, a key regulator of normal B cell development.Genetically reducing Ebf1 recapitulates some features of old pro-B cells.TADs that are most reduced with age also harbor genes important for function and development of pro-B cells, including the immunoglobulin heavy chain (IgH) gene locus.Weaker intra-TAD interactions at IgH correlate with reduced utilization of distally located variable gene segments in VDJ recombination.Our observations implicate 3D chromatin re-organization as a major driver of pro-B cell phenotypes that impair B lymphopoiesis with age.
Project description:The spatial arrangement of interphase chromosomes in the nucleus is important for gene expression and genome function in animals and in plants. The recently developed Hi-C technology is an efficacious method to investigate genome packing. Here we present a detailed Hi-C map of the three-dimensional genome organization of the plant Arabidopsis thaliana. We find that local chromatin packing differs from the patterns seen in animals, with kilobasepair-sized segments that have much higher intra-chromosome interaction rates than neighboring regions and which represent a dominant local structural feature of genome conformation in A. thaliana. These regions appear as positive strips on two-dimensional representations of chromatin interaction and they are enriched in epigenetic marks H3K27me3, H3.1 and H3.3. We also identify over 400 insulator-like regions. Furthermore, although topologically associating domains (TADs), which are prominent in animals, are not the dominant feature of A. thaliana genome packing, we found over 1,000 regions that have properties of TAD boundaries, and a similar number of regions similar to the interior of TADs. These insulator-like, TAD-boundary-like, and TAD-interior-like regions show strong enrichment for distinct epigenetic marks, and correlate with gene transcription levels. We conclude that epigenetic modifications, gene density, and transcriptional activity all contribute to shaping the local structure of the A. thaliana nuclear genome.