Limits...
Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters.

Gotter J, Brors B, Hergenhahn M, Kyewski B - J. Exp. Med. (2004)

Bottom Line: Analysis of promiscuous gene expression in purified stromal cells of the human thymus at the single and global gene level documents the species conservation of this phenomenon.Although there are no apparent structural or functional commonalities among these genes and their products, they cluster along chromosomes.These findings have implications for human autoimmune diseases, immuno-therapy of tumors, and the understanding of the nature of this unorthodox regulation of gene expression.

View Article: PubMed Central - PubMed

Affiliation: Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.

ABSTRACT
Promiscuous expression of tissue-specific self-antigens in the thymus imposes T cell tolerance and protects from autoimmune diseases, as shown in animal studies. Analysis of promiscuous gene expression in purified stromal cells of the human thymus at the single and global gene level documents the species conservation of this phenomenon. Medullary thymic epithelial cells overexpress a highly diverse set of genes (>400) including many tissue-specific antigens, disease-associated autoantigens, and cancer-germline genes. Although there are no apparent structural or functional commonalities among these genes and their products, they cluster along chromosomes. These findings have implications for human autoimmune diseases, immuno-therapy of tumors, and the understanding of the nature of this unorthodox regulation of gene expression.

Show MeSH

Related in: MedlinePlus

Genomic distribution of mTECs overexpressed genes. (a) Chromosomal assignment of genes overexpressed in mTECs versus cTECs. Pooled data from a female and a male donor have been analyzed. The relative distribution of all transcripts present on the chip with known chromosomal assignment was normalized to 1 for each chromosome. The absolute number of genes overexpressed in mTECs per chromosome is indicated above the bars. The relative distribution of mTECs genes shows no particular chromosomal preferences. n.d., not determined. (b) Distribution of the number of neighbors in 10,000 random gene lists that are located on the same chromosome within a distance of 200 kb (calculated from transcription start). The median and the 95th percentile of the distribution are marked by blue and green lines, respectively. The actually observed number in the list of 415 genes overexpressed in mTECs is indicated by a red line. (c) Number of clusters of size 2, 3, 4, and 5 within a window of 10 consecutive genes. The gray bars refer to the number in the list of genes overexpressed in mTECs and the white bars to the number in 1,000 random gene lists. The SD among these 1,000 lists is indicated by the error bar. (d) Clustered expression of 10 promiscuously expressed genes in mTECs within 5 Mbp on chromosome 1. SELENBP1, selenium binding protein 1; S100 A, calcium binding protein A; FLG, filaggrin; IVL, involucrin; SPRR1B, small proline rich protein 1B; NPR1, atrial natriuretic peptide receptor A; MUC1, mucin 1.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211762&req=5

fig4: Genomic distribution of mTECs overexpressed genes. (a) Chromosomal assignment of genes overexpressed in mTECs versus cTECs. Pooled data from a female and a male donor have been analyzed. The relative distribution of all transcripts present on the chip with known chromosomal assignment was normalized to 1 for each chromosome. The absolute number of genes overexpressed in mTECs per chromosome is indicated above the bars. The relative distribution of mTECs genes shows no particular chromosomal preferences. n.d., not determined. (b) Distribution of the number of neighbors in 10,000 random gene lists that are located on the same chromosome within a distance of 200 kb (calculated from transcription start). The median and the 95th percentile of the distribution are marked by blue and green lines, respectively. The actually observed number in the list of 415 genes overexpressed in mTECs is indicated by a red line. (c) Number of clusters of size 2, 3, 4, and 5 within a window of 10 consecutive genes. The gray bars refer to the number in the list of genes overexpressed in mTECs and the white bars to the number in 1,000 random gene lists. The SD among these 1,000 lists is indicated by the error bar. (d) Clustered expression of 10 promiscuously expressed genes in mTECs within 5 Mbp on chromosome 1. SELENBP1, selenium binding protein 1; S100 A, calcium binding protein A; FLG, filaggrin; IVL, involucrin; SPRR1B, small proline rich protein 1B; NPR1, atrial natriuretic peptide receptor A; MUC1, mucin 1.

Mentions: The chromosomal position of 415 of the 443 genes overexpressed in mTECs had been mapped. The relative distribution of these genes on the various chromosomes showed no marked under- or overrepresentation for particular chromosomes compared with the distribution of all mapped genes of the array (Fig. 4 a). Since the two datasets are from a male and a female thymus, we did not evaluate the Y chromosome. Notably, we did not find preferential X chromosomal locations as reported for genes expressed in spermatogonia, which partially overlap with genes expressed in mTECs (28, 29). Next, we analyzed whether promiscuously expressed genes are clustered along chromosomes. Recently, several studies in different species showed that genes coexpressed in a particular tissue are aligned in clusters (21, 30). We specifically calculated the probability with which 2 genes of the 415 gene pool would occur within a DNA window of 200 kb. This number was compared with the corresponding probabilities of 400 randomly sampled genes present on the arrays probing 10,000 permutations. There was a highly significant clustering of overexpressed genes (Fig. 4 b). This difference also holds when windows ranging between 35 and 5,000 kb were tested (not depicted). In addition, the experimental and random frequencies of 2, 3, 4, and 5 genes being clustered within a window of 10 adjacent genes present on the arrays irrespective of genetic distance has been calculated. This analysis revealed a clear overrepresentation of triplets and quadruplets in the experimental gene set compared with 1,000 random draws of the same number of genes (Fig. 4 c). An example of 10 genes clustered within 5 Mbp encompassing genes of different ontology, i.e., three members of the S100 gene family, MUC1 and SELENBP1, predominantly expressed in the liver (27) is shown in Fig. 4 d. We emphasize that we did not exclude homologous genes in this analysis, which may have arisen from gene duplication, since the expression pattern of individual members of such gene families may also reflect promiscuous gene expression. Thus, different type II keratin genes, including hair keratins were coexpressed in purified mTECs despite their differential regulation in epithelial cells of other tissues (31, 32).


Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters.

Gotter J, Brors B, Hergenhahn M, Kyewski B - J. Exp. Med. (2004)

Genomic distribution of mTECs overexpressed genes. (a) Chromosomal assignment of genes overexpressed in mTECs versus cTECs. Pooled data from a female and a male donor have been analyzed. The relative distribution of all transcripts present on the chip with known chromosomal assignment was normalized to 1 for each chromosome. The absolute number of genes overexpressed in mTECs per chromosome is indicated above the bars. The relative distribution of mTECs genes shows no particular chromosomal preferences. n.d., not determined. (b) Distribution of the number of neighbors in 10,000 random gene lists that are located on the same chromosome within a distance of 200 kb (calculated from transcription start). The median and the 95th percentile of the distribution are marked by blue and green lines, respectively. The actually observed number in the list of 415 genes overexpressed in mTECs is indicated by a red line. (c) Number of clusters of size 2, 3, 4, and 5 within a window of 10 consecutive genes. The gray bars refer to the number in the list of genes overexpressed in mTECs and the white bars to the number in 1,000 random gene lists. The SD among these 1,000 lists is indicated by the error bar. (d) Clustered expression of 10 promiscuously expressed genes in mTECs within 5 Mbp on chromosome 1. SELENBP1, selenium binding protein 1; S100 A, calcium binding protein A; FLG, filaggrin; IVL, involucrin; SPRR1B, small proline rich protein 1B; NPR1, atrial natriuretic peptide receptor A; MUC1, mucin 1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211762&req=5

fig4: Genomic distribution of mTECs overexpressed genes. (a) Chromosomal assignment of genes overexpressed in mTECs versus cTECs. Pooled data from a female and a male donor have been analyzed. The relative distribution of all transcripts present on the chip with known chromosomal assignment was normalized to 1 for each chromosome. The absolute number of genes overexpressed in mTECs per chromosome is indicated above the bars. The relative distribution of mTECs genes shows no particular chromosomal preferences. n.d., not determined. (b) Distribution of the number of neighbors in 10,000 random gene lists that are located on the same chromosome within a distance of 200 kb (calculated from transcription start). The median and the 95th percentile of the distribution are marked by blue and green lines, respectively. The actually observed number in the list of 415 genes overexpressed in mTECs is indicated by a red line. (c) Number of clusters of size 2, 3, 4, and 5 within a window of 10 consecutive genes. The gray bars refer to the number in the list of genes overexpressed in mTECs and the white bars to the number in 1,000 random gene lists. The SD among these 1,000 lists is indicated by the error bar. (d) Clustered expression of 10 promiscuously expressed genes in mTECs within 5 Mbp on chromosome 1. SELENBP1, selenium binding protein 1; S100 A, calcium binding protein A; FLG, filaggrin; IVL, involucrin; SPRR1B, small proline rich protein 1B; NPR1, atrial natriuretic peptide receptor A; MUC1, mucin 1.
Mentions: The chromosomal position of 415 of the 443 genes overexpressed in mTECs had been mapped. The relative distribution of these genes on the various chromosomes showed no marked under- or overrepresentation for particular chromosomes compared with the distribution of all mapped genes of the array (Fig. 4 a). Since the two datasets are from a male and a female thymus, we did not evaluate the Y chromosome. Notably, we did not find preferential X chromosomal locations as reported for genes expressed in spermatogonia, which partially overlap with genes expressed in mTECs (28, 29). Next, we analyzed whether promiscuously expressed genes are clustered along chromosomes. Recently, several studies in different species showed that genes coexpressed in a particular tissue are aligned in clusters (21, 30). We specifically calculated the probability with which 2 genes of the 415 gene pool would occur within a DNA window of 200 kb. This number was compared with the corresponding probabilities of 400 randomly sampled genes present on the arrays probing 10,000 permutations. There was a highly significant clustering of overexpressed genes (Fig. 4 b). This difference also holds when windows ranging between 35 and 5,000 kb were tested (not depicted). In addition, the experimental and random frequencies of 2, 3, 4, and 5 genes being clustered within a window of 10 adjacent genes present on the arrays irrespective of genetic distance has been calculated. This analysis revealed a clear overrepresentation of triplets and quadruplets in the experimental gene set compared with 1,000 random draws of the same number of genes (Fig. 4 c). An example of 10 genes clustered within 5 Mbp encompassing genes of different ontology, i.e., three members of the S100 gene family, MUC1 and SELENBP1, predominantly expressed in the liver (27) is shown in Fig. 4 d. We emphasize that we did not exclude homologous genes in this analysis, which may have arisen from gene duplication, since the expression pattern of individual members of such gene families may also reflect promiscuous gene expression. Thus, different type II keratin genes, including hair keratins were coexpressed in purified mTECs despite their differential regulation in epithelial cells of other tissues (31, 32).

Bottom Line: Analysis of promiscuous gene expression in purified stromal cells of the human thymus at the single and global gene level documents the species conservation of this phenomenon.Although there are no apparent structural or functional commonalities among these genes and their products, they cluster along chromosomes.These findings have implications for human autoimmune diseases, immuno-therapy of tumors, and the understanding of the nature of this unorthodox regulation of gene expression.

View Article: PubMed Central - PubMed

Affiliation: Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.

ABSTRACT
Promiscuous expression of tissue-specific self-antigens in the thymus imposes T cell tolerance and protects from autoimmune diseases, as shown in animal studies. Analysis of promiscuous gene expression in purified stromal cells of the human thymus at the single and global gene level documents the species conservation of this phenomenon. Medullary thymic epithelial cells overexpress a highly diverse set of genes (>400) including many tissue-specific antigens, disease-associated autoantigens, and cancer-germline genes. Although there are no apparent structural or functional commonalities among these genes and their products, they cluster along chromosomes. These findings have implications for human autoimmune diseases, immuno-therapy of tumors, and the understanding of the nature of this unorthodox regulation of gene expression.

Show MeSH
Related in: MedlinePlus