EBF1
Transcription factor COE1 (O/E-1) (OE-1) (Early B-cell factor) [COE1] [EBF]
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Having longer lived parents has been shown to be an important predictor of health trajectories and life span. As such, parental life span is an important phenotype that may uncover genes that affect longevity. A genome-wide association study of parental life span in participants of European and African ancestry from the Health and Retirement Study was conducted. A genome-wide significant association was observed for rs35715456 (log10BF = 6.3) on chromosome 18 for the dichotomous trait of having at least one long-lived parent versus not having any long-lived parent. This association was not replicated in an independent sample from the InCHIANTI and Framingham Heart Study. The most significant association among single nucleotide polymorphisms in longevity candidate genes (APOE, MINIPP1, FOXO3, EBF1, CAMKIV, and OTOL1) was observed in the EBF1 gene region (rs17056207, p = .0002). A promising genetic signal for parental life span was identified but was not replicated in independent samples.
MeSH Terms
- Aged
- Aged, 80 and over
- Chromosomes, Human, Pair 18
- Female
- Genome-Wide Association Study
- Humans
- Longevity
- Male
- Middle Aged
- Parents
- Phenotype
- Polymorphism, Single Nucleotide
- Trans-Activators
Keywords
- Epidemiology
- Genetics
- Life span
- Public health
- Successful aging
Precise understanding of radiation effects is critical to develop new modalities for the prevention and treatment of radiation-induced damage. We previously reported that non-lethal doses of X-ray irradiation induce DNA damage in human hematopoietic stem and progenitor cells (HSPCs) reconstituted in NOD/Shi-scid IL2rγnull (NOG) immunodeficient mice and severely compromise their repopulating capacity. In this study, we analyzed in detail the functional changes in human HSPCs in NOG mice following non-lethal radiation. We transplanted cord blood CD34 HSPCs into NOG mice. At 12 weeks post-transplantation, the recipients were irradiated with 0, 0.5, or 1.0 Gy. At 2 weeks post-irradiation, human CD34 HSPCs recovered from the primary recipient mice were transplanted into secondary recipients. CD34 HSPCs from irradiated mice showed severely impaired reconstitution capacity in the secondary recipient mice. Of interest, non-lethal radiation compromised contribution of HSPCs to the peripheral blood cells, particularly to CD19 B lymphocytes, which resulted in myeloid-biased repopulation. Co-culture of limiting numbers of CD34 HSPCs with stromal cells revealed that the frequency of B cell-producing CD34 HSPCs at 2 weeks post-irradiation was reduced more than 10-fold. Furthermore, the key B-cell regulator genes such as IL-7R and EBF1 were downregulated in HSPCs upon 0.5 Gy irradiation. Given that compromised repopulating capacity and myeloid-biased differentiation are representative phenotypes of aged HSCs, our findings indicate that non-lethal ionizing radiation is one of the critical external stresses that promote aging of human HSPCs in the bone marrow niche.
MeSH Terms
- Aging
- Animals
- B-Lymphocytes
- Cell Differentiation
- Gene Expression Regulation
- Hematopoiesis
- Hematopoietic Stem Cells
- Humans
- Mice, Inbred NOD
- Mice, SCID
- Phenotype
- Radiation, Ionizing
The number of circulating B-cells in peripheral blood plateaus between 2 and 24 months of age, and thereafter declines gradually. How this reflects the kinetics of the precursor B-cell pool in the bone marrow is of clinical interest, but has not been studied thoroughly in humans. The authors analyzed bone marrow (n = 37) from healthy children and adults (flow cytometry) searching for age-related changes in the total precursor B-cell compartment. In an age-matched cohort (n = 25) they examined age-related global gene expression changes (Affymetrix) in unsorted bone marrow with special reference to the recombination activating gene 1, RAG1. Subsequently, they searched the entire gene set for transcripts correlating to the RAG1 profile to discover other known and possibly new precursor B-cell related transcripts. Both methods disclosed a marked, transient increase of total precursor B-cells at 6-20 months, followed by a rapid decrease confined to the first 2 years. The decline thereafter was considerably slower, but continued until adulthood. The relative composition of total precursor B-cells, however, did not change significantly with age. The authors identified 54 genes that were highly correlated to the RAG1 profile (r >or= .9, p < 1 x 10(-8)). Of these 54 genes, 15 were characteristically B-lineage associated like CD19, CD79, VPREB, EBF1, and PAX5; the remaining 39 previously not described as distinctively B-lineage related. The marked, transient increase in precursor B-cells and RAG1 transcriptional activity is not reflected by a similar peak in B-cells in peripheral blood, whereas the sustained plateau concurs in time.
MeSH Terms
- Adolescent
- Adult
- Aging
- B-Lymphocyte Subsets
- Bone Marrow
- Bone Marrow Examination
- Cell Lineage
- Child
- Child, Preschool
- Cohort Studies
- Female
- Flow Cytometry
- Gene Expression Profiling
- Gene Expression Regulation, Developmental
- Hematopoietic Stem Cells
- Homeodomain Proteins
- Humans
- Infant
- Infant, Newborn
- Lymphocyte Count
- Male
- RNA, Messenger
- Transcription, Genetic
- Young Adult