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Epigenetic and genetic changes during mouse hematopoietic stem cell aging [RNA-Seq]

ABSTRACT: To investigate the global transcriptome changes in mouse hematopoietic stem cell aging, we performed high-throughput sequencing of Poly A+ RNA (RNA-Seq) from purified 4 month, and 24 month-old HSCs (SP-KSL-CD150+). With biological duplicates, more than 200 million reads in total for each age of HSC were obtained. Comparison of the young and old HSC transcriptomes revealed that 1,337 genes that were up-regulated, and 1,297 genes were down-regulated with HSC aging. The most highly represented upstream regulator was growth factor TGFB1, accounting for ~ 19% of differential gene expression in young versus old HSC (p-value = 1.96E-33). Gene ontology (GO) analyses indicated that up-regulated genes in 24mo HSCs are highly enriched in Regulation of Cell Adhesion, Regulation of Cell Proliferation and Ribosome, while down-regulated genes are enriched in DNA Base Excision Repair, DNA replication and Cell Cycle. RNA-seq also allowed us to examine alternative isoforms with aging including alternative splicing, promoter usage and pre-mRNA abundance.

ORGANISM(S): Mus musculus

PROVIDER: GSE47817 | GEO | 2014/04/30

SECONDARY ACCESSION(S): PRJNA208010

REPOSITORIES: GEO

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Epigenetic and genetic changes during mouse hematopoietic stem cell aging [RNA-Seq]

Project description:To investigate the global transcriptome changes in mouse hematopoietic stem cell aging, we performed high-throughput sequencing of Poly A+ RNA (RNA-Seq) from purified 4 month, and 24 month-old HSCs (SP-KSL-CD150+). With biological duplicates, more than 200 million reads in total for each age of HSC were obtained. Comparison of the young and old HSC transcriptomes revealed that 1,337 genes that were up-regulated, and 1,297 genes were down-regulated with HSC aging. The most highly represented upstream regulator was growth factor TGFB1, accounting for ~ 19% of differential gene expression in young versus old HSC (p-value = 1.96E-33). Gene ontology (GO) analyses indicated that up-regulated genes in 24mo HSCs are highly enriched in Regulation of Cell Adhesion, Regulation of Cell Proliferation and Ribosome, while down-regulated genes are enriched in DNA Base Excision Repair, DNA replication and Cell Cycle. RNA-seq also allowed us to examine alternative isoforms with aging including alternative splicing, promoter usage and pre-mRNA abundance. Mouse hematopoietic stem cell mRNA profiles of 4 month and 24 month old WT mice were generated generated by deep sequencing, in duplicate, using Illumina Hiseq 2000

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Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response [3]

Project description:The bone marrow (BM) niche comprised of BM endothelial cells (BMECs) and LepR+ mesenchymal stromal cells (MSCs), plays a critical role in preserving the fitness of hematopoietic stem cells (HSCs). Aging is associated with defects in the BM niche that impair their ability to support HSC activity. However, mechanisms underlying age-related defects in the BM niche remain poorly understood. In this study, we identify BM niche derived Netrin-1 (NTN1) as a critical regulator of BM niche cell fitness during aging. Conditional deletion of NTN-1 specifically within BM MSCs or BMECs of young mice resulted in premature aging phenotypes within the BM niche including increased vascular leakiness, hypoxia, DNA damage and adiposity. On the other hand, supplementation of aged mice with NTN1 resulted in restoration of these hallmark niche defects and a rejuvenation of HSC activity. Mechanistically, we identify NTN1 as a critical regulator of DNA Damage Response (DDR) within BM niche cells and HSCs. In this experiment, RNA Seq analysis was performed on BMECs derived from young (3 month old) and aged (18 month old) mice to characterize transcriptional alterations within BMECs during aging.

2023-04-14 | GSE227145 | GEO

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Project description:The bone marrow (BM) niche comprised of BM endothelial cells (BMECs) and LepR+ mesenchymal stromal cells (MSCs), plays a critical role in preserving the fitness of hematopoietic stem cells (HSCs). Aging is associated with defects in the BM niche that impair their ability to support HSC activity. However, mechanisms underlying age-related defects in the BM niche remain poorly understood. In this study, we identify BM niche derived Netrin-1 (NTN1) as a critical regulator of BM niche cell fitness during aging. Conditional deletion of NTN-1 specifically within BM MSCs or BMECs of young mice resulted in premature aging phenotypes within the BM niche including increased vascular leakiness, hypoxia, DNA damage and adiposity. On the other hand, supplementation of aged mice with NTN1 resulted in restoration of these hallmark niche defects and a rejuvenation of HSC activity. Mechanistically, we identify NTN1 as a critical regulator of DNA Damage Response (DDR) within BM niche cells and HSCs. In this experiment, RNA Seq analysis was performed on BM MSCs derived from young (3 month old) and aged (18 month old) mice to characterize transcriptional alterations within BM MSCs during aging.

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