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Basic leucine zipper transcriptional factor ATF-like (B-cell-activating transcription factor) (B-ATF) (SF-HT-activated gene 2 protein) (SFA-2)


LncRNA-ES3 inhibition by Bhlhe40 is involved in high glucose-induced calcification/senescence of vascular smooth muscle cells.

Long noncoding RNAs (lncRNAs) have been investigated as novel regulatory molecules involved in diverse biological processes. Our previous study demonstrated that lncRNA-ES3 is associated with the high glucose-induced calcification/senescence of human aortic vascular smooth muscle cells (HA-VSMCs). However, the mechanism of lncRNA-ES3 in vascular calcification/aging remained largely unknown. Here, we report that the expression of basic helix-loop-helix family member e40 (Bhlhe40) was decreased significantly in HA-VSMCs treated with high glucose, whereas the expression of basic leucine zipper transcription factor (BATF) was increased. Overexpression of Bhlhe40 and inhibition of BATF alleviated calcification/senescence of HA-VSMCs, as confirmed by Alizarin Red S staining and the presence of senescence-associated β-galactosidase-positive cells. Moreover, we identified that Bhlhe40 regulates lncRNA-ES3 in HA-VSMCs by binding to the promoter region of the lncRNA-ES3 gene (LINC00458). Upregulation or inhibition of lncRNA-ES3 expression significantly promoted or reduced calcification/senescence of HA-VSMCs, respectively. Additionally, we identified that lncRNA-ES3 functions in this process by suppressing the expression of miR-95-5p, miR-6776-5p, miR-3620-5p, and miR-4747-5p. The results demonstrate that lncRNA-ES3 triggers gene silencing of multiple miRNAs by binding to Bhlhe40, leading to calcification/senescence of VSMCs. Our findings suggest that pharmacological interventions targeting lncRNA-ES3 may be therapeutically beneficial in ameliorating vascular calcification/aging.


  • Bhlhe40
  • VSMC calcification/senescence
  • diabetes
  • lncRNA-ES3
  • microRNA
  • vascular aging

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation.

With reduced thymic activity, the population of naïve T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, naïve CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether naïve CD4 T-cell aging is associated with a partial loss of this unbiased multipotency. We find that naïve CD4 T cells from older individuals have developed a propensity to develop into TH9 cells. Two major mechanisms contribute to this predisposition. First, responsiveness to transforming growth factor β (TGFβ) stimulation is enhanced with age due to an upregulation of the TGFβR3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged naïve CD4 T cells display altered transcription factor profiles in response to T-cell receptor stimulation, including enhanced expression of BATF and IRF4 and reduced expression of ID3 and BCL6. These transcription factors are involved in TH9 differentiation as well as IL9 transcription suggesting that the aging-associated changes in the transcription factor profile favor TH9 commitment.

MeSH Terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Basic-Leucine Zipper Transcription Factors
  • Blood Donors
  • CD4-Positive T-Lymphocytes
  • Cell Differentiation
  • Female
  • HEK293 Cells
  • Healthy Volunteers
  • Humans
  • Inhibitor of Differentiation Proteins
  • Interferon Regulatory Factors
  • Interleukin-9
  • Male
  • Middle Aged
  • Neoplasm Proteins
  • Proteoglycans
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-6
  • Receptors, Antigen, T-Cell
  • Receptors, Transforming Growth Factor beta
  • T-Lymphocytes, Helper-Inducer
  • Trans-Activators
  • Transfection
  • Young Adult


  • T-cell lineage differentiation
  • aging
  • immunosenescence
  • interleukin 9
  • multipotency
  • transforming growth factor β

Transcriptomic analysis of human IL-7 receptor alpha and effector memory CD8 T cells reveals an age-associated signature linked to influenza vaccine response in older adults.

Here, we investigated the relationship of the age-associated expansion of IL-7 receptor alpha low (IL-7Rα ) effector memory (EM) CD8 T cells with the global transcriptomic profile of peripheral blood cells in humans. We found 231 aging signature genes of IL-7Rα EM CD8 T cells that corresponded to 15% of the age-associated genes (231/1,497) reported by a meta-analysis study on human peripheral whole blood from approximately 15,000 individuals, having high correlation with chronological age. These aging signature genes were the target genes of several transcription factors including MYC, SATB1, and BATF, which also belonged to the 231 genes, supporting the upstream regulatory role of these transcription factors in altering the gene expression profile of peripheral blood cells with aging. We validated the differential expression of these transcription factors between IL-7Rα and EM CD8 T cells as well as in peripheral blood mononuclear cells (PBMCs) of young and older adults. Finally, we found a significant association with influenza vaccine responses in older adults, suggesting the possible biological significance of the aging signature genes of IL-7Rα EM CD8 T cells. The results of our study support the relationship of the expansion of IL-7Rα EM CD8 T cells with the age-associated changes in the gene expression profile of peripheral blood cells and its possible biological implications.

MeSH Terms

  • Adult
  • Aged
  • Aging
  • CD8-Positive T-Lymphocytes
  • Cohort Studies
  • Female
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Healthy Volunteers
  • Humans
  • Immunologic Memory
  • Influenza Vaccines
  • Male
  • Middle Aged
  • Receptors, Interleukin-7
  • Transcription Factors
  • Transcriptome
  • Young Adult


  • IL-7 receptor alpha
  • age
  • gene expression
  • human
  • memory CD8 T cells
  • vaccine response