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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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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. 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

ORGANISM(S): Mus musculus

SUBMITTER: deqiang sun

PROVIDER: E-GEOD-47817 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

2014-04-30 | GSE47817 | GEO

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

Project description:To investigate the global DNA methylation changes in mouse hematopoietic stem cell aging, we performed whole-genome bisulfite sequencing (WGBS). We generated 1,494 million (4mo HSCs), and 1,493 million (24mo HSCs) raw reads; about 82.6% and 84.3%, respectively, were successfully aligned to either strand of the reference genome (mm9). Of all the cytosines present in the reference genome sequence, about 93% of Cs and 99% of CGs were covered in both datasets, with an average coverage of 46-fold (4mo) and 50-fold (24mo). In contrast to the age-associated hypomethylation observed in studies of somatic cells, mentioned above, HSCs showed an increase of methylation with age. The average methylation level over all 16 million covered CpGs increased from 83.5% in young (4mo) HSC to 84.6% in old (24mo) HSC. We observed a total of 448,166 differentially methylated CpGs (DMCs), defined as those having a 20% or more difference in methylation ratio, of which 38.5% (172,609) were hypomethylated (hypo-DMCs) and 61.5% (275,557) were hypermethylated (hyper-DMCs) with aging. For different genomic features, a slightly greater DNA methylation ratio increase was observed for the gene body, LINEs and SINEs, while CGIs and promoters showed balanced increases and decreases. Localization analysis of DMCs indicates that DNA encoding for ribosome RNA (rDNA) is primarily a hotspot for hypo-DMCs, while promoters without CpG islands, CpG island shores and LINE repetitive elements exhibit both hypo- and hyper-DMCs. Mouse hematopoietic stem cell DNA methylation profiles of 4 month and 24 month old WT mice were generated generated by deep sequencing, in duplicate, using Illumina Hiseq 2000.

2014-04-30 | E-GEOD-47815 | biostudies-arrayexpress

Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response [4]

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 HSCs derived from young mice (3 month old), PBS treated aged mice (18 month old), and NTN1 treated aged mice (18 month old), to characterize transcriptional alterations within HSCs during aging, and following NTN1 treatment of aged mice.

2023-04-14 | GSE227146 | GEO

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

Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response [2]

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.

2023-04-14 | GSE227144 | GEO

Loss of Phf6 prevents aging associated transcriptomic profile changes in LT-HSCs

Project description:Loss of Phf6 prevents the functional decline and immunophenotypic changes associated with age-related, long-term repopulating hematopoietic stem cell (LT-HSC) exhaustion. To identify the underlying molecular mechanisms that account for these differences, we performed RNA-seq profiling of LT-HSCs isolated from the bone marrow of Phf6 wild-type and knock-out, young (16-week-old) and aged (24-month-old) C57BL/6 mice. Our analysis revealed that LT-HSCs isolated from 24-month-old, Phf6 knockout mice retained the molecular signatures associated with young LT-HSCs whereas LT-HSCs isolated from aged, Phf6 wild-type mice acquired signatures consistent with HSC exhaustion. Mechanistically, these data revealed important roles for key metabolic pathways including glutathione metabolism and sterol biosynthesis, as well as cell-cell interaction and signaling pathways such as the interferon and TGF-beta responses.

2022-11-01 | GSE165695 | GEO

Bulk and single RNA sequencing on the role of Igf2bp2 in myeloid-biased HSC

Project description:Using RNA sequencing analysis on myeloid biased HSC, we compared gene expression profiles between WT and Igf2bp2 knock-out mice at young and old age. 1421 differentially expressed genes were identified in young myeloid biased HSC from Igf2bp2 knock-out mice compared to young WT; however, only 26 differentially expressed genes were identified in old myeloid biased HSC from Igf2bp2 knock-out mice compared to old WT. Compared to young WT myeloid biased HSC, myeloid biased HSC from young Igf2bp2 knock-out exhibits reduced expression of genes involved in metabolism and translation. In addition, single cell RNA sequencing analysis of myeloid biased HSC in young wildtype mice identified nine sub-clusters. HSCs from a sub-cluster with high expression of Igf2bp2 exhibit up-regulated IGF/PI3K/AKT signaling and increased expression of genes involved in HSC quiescence and maintenance. Altogether, the study provides a correlation and mechanism to understand the role of Igf2bp2 in HSC function and aging.

2021-02-05 | GSE166176 | GEO

Young and old HSCs from WT and Lnk-/- mice

Project description:The adaptor protein Lnk is an important negative regulator of HSC homeostasis and self-renewal. This study aims to investigate the role of Lnk in HSC aging. Here we performed expression profiling of bone marrow CD150+CD48-LSK LT-HSCs from young and old WT and Lnk-/- mice. Results identify select Lnk-mediated pathways with potential involvement in HSC self-renewal and aging. CD150+CD48-LSK HSCs were double sorted from WT and Lnk-/- mice at both young and old ages (2 months and 20 months, respectively). RNA was isolated using miRNeasy kit from QIAGEN and processed using the NuGEN Pico kit. The microarray analysis was performed at the Penn Molecular Profiling/Genomics Facility using GeneChip Mouse Gene 1.0ST array (Affymetrix).

2012-10-03 | E-GEOD-39553 | biostudies-arrayexpress

p38α plays differential roles in hematopoietic stem cell activity dependent on aging contexts

Project description:Hematopoietic stem cells (HSCs) and their progeny sustain lifetime hematopoiesis. Aging alters HSC function, number, and composition and increases risk of hematological malignancies, but how these changes occur in HSCs remains unclear. Signaling via p38MAPK has been proposed as a candidate mechanism underlying induction of HSC aging. Here, using genetic models of both chronological and premature aging, we describe a multimodal role for p38α, the major p38MAPK isozyme in hematopoiesis, in HSC aging. We report that p38α regulates differentiation bias and sustains transplantation capacity of HSCs in the early phase of chronological aging (from young to 1-year-old). However, p38α decreased HSC transplantation capacity in the late progression phase of chronological aging (from 1- to 2-years-old). Furthermore, co-deletion of p38α in mice deficient in Ataxia-telangiectasia mutated (Atm), a model of premature aging, exacerbated aging-related HSC phenotypes seen in Atm single mutant mice. Mechanistically, p38α makes a positive contribution to inflammation during the late phase aging, resulting in defects in 2-year-old HSCs. Overall, we propose multiple functions of p38MAPK, which both promotes and suppresses HSC aging context-dependently.

2021-03-03 | GSE168057 | GEO

p38α plays differential roles in hematopoietic stem cell activity dependent on aging contexts II

2021-03-03 | GSE168085 | GEO

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