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Age-Related Gene Expression Differences in Monocytes from Human Neonates, Young Adults, and Older Adults.

Lissner MM, Thomas BJ, Wee K, Tong AJ, Kollmann TR, Smale ST - PLoS ONE (2015)

Bottom Line: A variety of age-related differences in the innate and adaptive immune systems have been proposed to contribute to the increased susceptibility to infection of human neonates and older adults.By examining the differentially induced genes in the context of transcription factor binding motifs and RNA-seq data sets from mutant mouse strains, a previously described deficiency in interferon response factor-3 activity could be implicated in most of the differences between newborns and young adults.Contrary to these observations, older adults exhibited elevated expression of inflammatory genes at baseline, yet the responses following stimulation correlated more closely with those observed in younger adults.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.

ABSTRACT
A variety of age-related differences in the innate and adaptive immune systems have been proposed to contribute to the increased susceptibility to infection of human neonates and older adults. The emergence of RNA sequencing (RNA-seq) provides an opportunity to obtain an unbiased, comprehensive, and quantitative view of gene expression differences in defined cell types from different age groups. An examination of ex vivo human monocyte responses to lipopolysaccharide stimulation or Listeria monocytogenes infection by RNA-seq revealed extensive similarities between neonates, young adults, and older adults, with an unexpectedly small number of genes exhibiting statistically significant age-dependent differences. By examining the differentially induced genes in the context of transcription factor binding motifs and RNA-seq data sets from mutant mouse strains, a previously described deficiency in interferon response factor-3 activity could be implicated in most of the differences between newborns and young adults. Contrary to these observations, older adults exhibited elevated expression of inflammatory genes at baseline, yet the responses following stimulation correlated more closely with those observed in younger adults. Notably, major differences in the expression of constitutively expressed genes were not observed, suggesting that the age-related differences are driven by environmental influences rather than cell-autonomous differences in monocyte development.

No MeSH data available.


Related in: MedlinePlus

Hierarchical clustering of LPS-stimulated monocyte transcriptomes from human neonates, adults, and older adults.(A) RNA-seq experiments were performed with three independent human monocyte samples from cord blood (N), young adult peripheral blood (A), and older adult peripheral blood (OA) stimulated with LPS for 0, 1, and 6 hrs. Hierarchical clustering was performed with the 1147 genes found to be induced by at least 5-fold at the 1- or 6-hr time point in at least one sample and with an induced RPKM of at least 4 (genes smaller than 200 bp were also excluded from the analysis). Sample codes correspond to the age abbreviation followed by the sample number (1 through 3 for each age); the time point (0, 1, or 6 hr) is indicated after the period. Inducible transcriptomes exhibit strong time-dependent clustering, with much less age-dependent clustering. (B) Pearson correlation values (R) used for the hierarchical clustering in panel A are shown. Each time point from each sample was compared to every other sample and time point. R values are color-coded from low (green) to high (red). Samples on the X and Y axes are grouped first according to age group, then time point (0, 1, or 6), and then sample number (1–3).
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pone.0132061.g001: Hierarchical clustering of LPS-stimulated monocyte transcriptomes from human neonates, adults, and older adults.(A) RNA-seq experiments were performed with three independent human monocyte samples from cord blood (N), young adult peripheral blood (A), and older adult peripheral blood (OA) stimulated with LPS for 0, 1, and 6 hrs. Hierarchical clustering was performed with the 1147 genes found to be induced by at least 5-fold at the 1- or 6-hr time point in at least one sample and with an induced RPKM of at least 4 (genes smaller than 200 bp were also excluded from the analysis). Sample codes correspond to the age abbreviation followed by the sample number (1 through 3 for each age); the time point (0, 1, or 6 hr) is indicated after the period. Inducible transcriptomes exhibit strong time-dependent clustering, with much less age-dependent clustering. (B) Pearson correlation values (R) used for the hierarchical clustering in panel A are shown. Each time point from each sample was compared to every other sample and time point. R values are color-coded from low (green) to high (red). Samples on the X and Y axes are grouped first according to age group, then time point (0, 1, or 6), and then sample number (1–3).

Mentions: An examination of the data sets from the LPS experiment identified 1147 annotated RefSeq genes that were induced by at least five-fold at the 1- or 6-hr time point (relative to the unstimulated sample) in at least one sample from any age group, and that exhibited a transcript level exceeding four RPKM following induction. To examine the relationship between the different time points and age groups in the response to LPS, hierarchical clustering was performed with these 1147 genes (Fig 1A). This analysis revealed that each of the nine samples from a given time point was more closely related to the other samples from the same time point than to any sample from the other two time-points. The most significant difference that showed a possible relationship to age was that the three unstimulated samples from older adults (OA1.0, OA2.0, and OA3.0) and one young adult unstimulated sample (A1.0) clustered separately from the remaining unstimulated samples from young adults and neonates.


Age-Related Gene Expression Differences in Monocytes from Human Neonates, Young Adults, and Older Adults.

Lissner MM, Thomas BJ, Wee K, Tong AJ, Kollmann TR, Smale ST - PLoS ONE (2015)

Hierarchical clustering of LPS-stimulated monocyte transcriptomes from human neonates, adults, and older adults.(A) RNA-seq experiments were performed with three independent human monocyte samples from cord blood (N), young adult peripheral blood (A), and older adult peripheral blood (OA) stimulated with LPS for 0, 1, and 6 hrs. Hierarchical clustering was performed with the 1147 genes found to be induced by at least 5-fold at the 1- or 6-hr time point in at least one sample and with an induced RPKM of at least 4 (genes smaller than 200 bp were also excluded from the analysis). Sample codes correspond to the age abbreviation followed by the sample number (1 through 3 for each age); the time point (0, 1, or 6 hr) is indicated after the period. Inducible transcriptomes exhibit strong time-dependent clustering, with much less age-dependent clustering. (B) Pearson correlation values (R) used for the hierarchical clustering in panel A are shown. Each time point from each sample was compared to every other sample and time point. R values are color-coded from low (green) to high (red). Samples on the X and Y axes are grouped first according to age group, then time point (0, 1, or 6), and then sample number (1–3).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4493075&req=5

pone.0132061.g001: Hierarchical clustering of LPS-stimulated monocyte transcriptomes from human neonates, adults, and older adults.(A) RNA-seq experiments were performed with three independent human monocyte samples from cord blood (N), young adult peripheral blood (A), and older adult peripheral blood (OA) stimulated with LPS for 0, 1, and 6 hrs. Hierarchical clustering was performed with the 1147 genes found to be induced by at least 5-fold at the 1- or 6-hr time point in at least one sample and with an induced RPKM of at least 4 (genes smaller than 200 bp were also excluded from the analysis). Sample codes correspond to the age abbreviation followed by the sample number (1 through 3 for each age); the time point (0, 1, or 6 hr) is indicated after the period. Inducible transcriptomes exhibit strong time-dependent clustering, with much less age-dependent clustering. (B) Pearson correlation values (R) used for the hierarchical clustering in panel A are shown. Each time point from each sample was compared to every other sample and time point. R values are color-coded from low (green) to high (red). Samples on the X and Y axes are grouped first according to age group, then time point (0, 1, or 6), and then sample number (1–3).
Mentions: An examination of the data sets from the LPS experiment identified 1147 annotated RefSeq genes that were induced by at least five-fold at the 1- or 6-hr time point (relative to the unstimulated sample) in at least one sample from any age group, and that exhibited a transcript level exceeding four RPKM following induction. To examine the relationship between the different time points and age groups in the response to LPS, hierarchical clustering was performed with these 1147 genes (Fig 1A). This analysis revealed that each of the nine samples from a given time point was more closely related to the other samples from the same time point than to any sample from the other two time-points. The most significant difference that showed a possible relationship to age was that the three unstimulated samples from older adults (OA1.0, OA2.0, and OA3.0) and one young adult unstimulated sample (A1.0) clustered separately from the remaining unstimulated samples from young adults and neonates.

Bottom Line: A variety of age-related differences in the innate and adaptive immune systems have been proposed to contribute to the increased susceptibility to infection of human neonates and older adults.By examining the differentially induced genes in the context of transcription factor binding motifs and RNA-seq data sets from mutant mouse strains, a previously described deficiency in interferon response factor-3 activity could be implicated in most of the differences between newborns and young adults.Contrary to these observations, older adults exhibited elevated expression of inflammatory genes at baseline, yet the responses following stimulation correlated more closely with those observed in younger adults.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America.

ABSTRACT
A variety of age-related differences in the innate and adaptive immune systems have been proposed to contribute to the increased susceptibility to infection of human neonates and older adults. The emergence of RNA sequencing (RNA-seq) provides an opportunity to obtain an unbiased, comprehensive, and quantitative view of gene expression differences in defined cell types from different age groups. An examination of ex vivo human monocyte responses to lipopolysaccharide stimulation or Listeria monocytogenes infection by RNA-seq revealed extensive similarities between neonates, young adults, and older adults, with an unexpectedly small number of genes exhibiting statistically significant age-dependent differences. By examining the differentially induced genes in the context of transcription factor binding motifs and RNA-seq data sets from mutant mouse strains, a previously described deficiency in interferon response factor-3 activity could be implicated in most of the differences between newborns and young adults. Contrary to these observations, older adults exhibited elevated expression of inflammatory genes at baseline, yet the responses following stimulation correlated more closely with those observed in younger adults. Notably, major differences in the expression of constitutively expressed genes were not observed, suggesting that the age-related differences are driven by environmental influences rather than cell-autonomous differences in monocyte development.

No MeSH data available.


Related in: MedlinePlus