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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

Genes that exhibit the greatest expression deficit in LPS-stimulated cord blood monocytes in comparison to adult monocytes are regulated by IRF3 and/or Type I IFNs.(A) LPS-induced genes exhibiting statistically significant differential expression in neonates and adults (n = 118) were grouped according to the time point at which their maximum transcript levels were observed (1 or 6 hrs). They were then grouped according to their relative maximum transcript levels in cord blood (neonates) versus young adults. Induced genes with a higher maximum transcript level in neonates than young adults (with statistically significant differential expression) are included in classes I (1-hr peak) and III (6-hr peak) (column 7). Genes exhibiting a maximum transcript level in neonates that was 50–100% of the young adult transcript level (but with statistically significant differential expression) are included in class IV (no genes with peak transcript levels at 1-hr fit this criterion). Genes exhibiting a maximum transcript level in neonates that was 20–50% of the young adult transcript level are in classes II (1-hr) and V (6-hr). Genes with a maximum transcript level in neonates below 20% of the young adult transcript level are in class VI. The differential expression of six of these genes was confirmed by quantitative RT-PCR (data not shown). Columns 1–6 show the relative transcript levels (based on the log-transformed mean-centered RPKM) for these 118 classified genes in all samples and all time points from both neonates and young adults. Column 8 indicates genes that lack obvious mouse orthologs (lightest pink), genes that contain mouse orthologs that are either not expressed or not induced in mouse bone marrow-derived macrophages (dark pink), and genes containing mouse orthologs that are both expressed and induced by LPS (red). Columns 9 and 10 show relative expression of the mouse ortholog of the human gene in Lipid A-stimulated macrophages from IRF3-/- and IFNAR-/- mice, respectively (see blue scale at right). Note that these columns are only relevant for genes shown in red in Column 8. Column 11 indicates genes with promoters that contain an IRF1 transcription factor binding motif between -450 and +50 bps relative to the transcription start site. (B) Enrichment of transcription factor binding sites determined using the Pscan program is shown for each gene class from panel A. Color intensity is proportional to the negative log(p-value).
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pone.0132061.g005: Genes that exhibit the greatest expression deficit in LPS-stimulated cord blood monocytes in comparison to adult monocytes are regulated by IRF3 and/or Type I IFNs.(A) LPS-induced genes exhibiting statistically significant differential expression in neonates and adults (n = 118) were grouped according to the time point at which their maximum transcript levels were observed (1 or 6 hrs). They were then grouped according to their relative maximum transcript levels in cord blood (neonates) versus young adults. Induced genes with a higher maximum transcript level in neonates than young adults (with statistically significant differential expression) are included in classes I (1-hr peak) and III (6-hr peak) (column 7). Genes exhibiting a maximum transcript level in neonates that was 50–100% of the young adult transcript level (but with statistically significant differential expression) are included in class IV (no genes with peak transcript levels at 1-hr fit this criterion). Genes exhibiting a maximum transcript level in neonates that was 20–50% of the young adult transcript level are in classes II (1-hr) and V (6-hr). Genes with a maximum transcript level in neonates below 20% of the young adult transcript level are in class VI. The differential expression of six of these genes was confirmed by quantitative RT-PCR (data not shown). Columns 1–6 show the relative transcript levels (based on the log-transformed mean-centered RPKM) for these 118 classified genes in all samples and all time points from both neonates and young adults. Column 8 indicates genes that lack obvious mouse orthologs (lightest pink), genes that contain mouse orthologs that are either not expressed or not induced in mouse bone marrow-derived macrophages (dark pink), and genes containing mouse orthologs that are both expressed and induced by LPS (red). Columns 9 and 10 show relative expression of the mouse ortholog of the human gene in Lipid A-stimulated macrophages from IRF3-/- and IFNAR-/- mice, respectively (see blue scale at right). Note that these columns are only relevant for genes shown in red in Column 8. Column 11 indicates genes with promoters that contain an IRF1 transcription factor binding motif between -450 and +50 bps relative to the transcription start site. (B) Enrichment of transcription factor binding sites determined using the Pscan program is shown for each gene class from panel A. Color intensity is proportional to the negative log(p-value).

Mentions: The 118 genes (gene identities listed in S1 Fig) were separated into groups according to the time point at which their maximum mRNA level was observed (Fig 5A: 1-hr peak expression for Groups I and II; 6-hr peak expression for Groups III-VI). The genes were then further grouped according to their expression level in neonates relative to their expression level in young adults (Fig 5A, column 7). (For this calculation, the baseline and maximum expression levels in young adults were defined as 0% and 100%, respectively; the maximum expression level in neonates was then determined as a percentage relative to that range.) This analysis revealed 35 genes that exhibited enhanced expression in the neonatal samples (Groups I and III, lightest shade of purple) and 83 genes that exhibited reduced expression (Groups II, IV, V, and VI, three darker shades of purple). Group VI contains the 34 genes that exhibited the greatest difference between neonates and young adults. For these genes, the maximum LPS-induced mRNA level in neonates was less than 20% of the maximum level observed in young adults.


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)

Genes that exhibit the greatest expression deficit in LPS-stimulated cord blood monocytes in comparison to adult monocytes are regulated by IRF3 and/or Type I IFNs.(A) LPS-induced genes exhibiting statistically significant differential expression in neonates and adults (n = 118) were grouped according to the time point at which their maximum transcript levels were observed (1 or 6 hrs). They were then grouped according to their relative maximum transcript levels in cord blood (neonates) versus young adults. Induced genes with a higher maximum transcript level in neonates than young adults (with statistically significant differential expression) are included in classes I (1-hr peak) and III (6-hr peak) (column 7). Genes exhibiting a maximum transcript level in neonates that was 50–100% of the young adult transcript level (but with statistically significant differential expression) are included in class IV (no genes with peak transcript levels at 1-hr fit this criterion). Genes exhibiting a maximum transcript level in neonates that was 20–50% of the young adult transcript level are in classes II (1-hr) and V (6-hr). Genes with a maximum transcript level in neonates below 20% of the young adult transcript level are in class VI. The differential expression of six of these genes was confirmed by quantitative RT-PCR (data not shown). Columns 1–6 show the relative transcript levels (based on the log-transformed mean-centered RPKM) for these 118 classified genes in all samples and all time points from both neonates and young adults. Column 8 indicates genes that lack obvious mouse orthologs (lightest pink), genes that contain mouse orthologs that are either not expressed or not induced in mouse bone marrow-derived macrophages (dark pink), and genes containing mouse orthologs that are both expressed and induced by LPS (red). Columns 9 and 10 show relative expression of the mouse ortholog of the human gene in Lipid A-stimulated macrophages from IRF3-/- and IFNAR-/- mice, respectively (see blue scale at right). Note that these columns are only relevant for genes shown in red in Column 8. Column 11 indicates genes with promoters that contain an IRF1 transcription factor binding motif between -450 and +50 bps relative to the transcription start site. (B) Enrichment of transcription factor binding sites determined using the Pscan program is shown for each gene class from panel A. Color intensity is proportional to the negative log(p-value).
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Related In: Results  -  Collection

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pone.0132061.g005: Genes that exhibit the greatest expression deficit in LPS-stimulated cord blood monocytes in comparison to adult monocytes are regulated by IRF3 and/or Type I IFNs.(A) LPS-induced genes exhibiting statistically significant differential expression in neonates and adults (n = 118) were grouped according to the time point at which their maximum transcript levels were observed (1 or 6 hrs). They were then grouped according to their relative maximum transcript levels in cord blood (neonates) versus young adults. Induced genes with a higher maximum transcript level in neonates than young adults (with statistically significant differential expression) are included in classes I (1-hr peak) and III (6-hr peak) (column 7). Genes exhibiting a maximum transcript level in neonates that was 50–100% of the young adult transcript level (but with statistically significant differential expression) are included in class IV (no genes with peak transcript levels at 1-hr fit this criterion). Genes exhibiting a maximum transcript level in neonates that was 20–50% of the young adult transcript level are in classes II (1-hr) and V (6-hr). Genes with a maximum transcript level in neonates below 20% of the young adult transcript level are in class VI. The differential expression of six of these genes was confirmed by quantitative RT-PCR (data not shown). Columns 1–6 show the relative transcript levels (based on the log-transformed mean-centered RPKM) for these 118 classified genes in all samples and all time points from both neonates and young adults. Column 8 indicates genes that lack obvious mouse orthologs (lightest pink), genes that contain mouse orthologs that are either not expressed or not induced in mouse bone marrow-derived macrophages (dark pink), and genes containing mouse orthologs that are both expressed and induced by LPS (red). Columns 9 and 10 show relative expression of the mouse ortholog of the human gene in Lipid A-stimulated macrophages from IRF3-/- and IFNAR-/- mice, respectively (see blue scale at right). Note that these columns are only relevant for genes shown in red in Column 8. Column 11 indicates genes with promoters that contain an IRF1 transcription factor binding motif between -450 and +50 bps relative to the transcription start site. (B) Enrichment of transcription factor binding sites determined using the Pscan program is shown for each gene class from panel A. Color intensity is proportional to the negative log(p-value).
Mentions: The 118 genes (gene identities listed in S1 Fig) were separated into groups according to the time point at which their maximum mRNA level was observed (Fig 5A: 1-hr peak expression for Groups I and II; 6-hr peak expression for Groups III-VI). The genes were then further grouped according to their expression level in neonates relative to their expression level in young adults (Fig 5A, column 7). (For this calculation, the baseline and maximum expression levels in young adults were defined as 0% and 100%, respectively; the maximum expression level in neonates was then determined as a percentage relative to that range.) This analysis revealed 35 genes that exhibited enhanced expression in the neonatal samples (Groups I and III, lightest shade of purple) and 83 genes that exhibited reduced expression (Groups II, IV, V, and VI, three darker shades of purple). Group VI contains the 34 genes that exhibited the greatest difference between neonates and young adults. For these genes, the maximum LPS-induced mRNA level in neonates was less than 20% of the maximum level observed in young adults.

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