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TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program.

Choi J, Southworth LK, Sarin KY, Venteicher AS, Ma W, Chang W, Cheung P, Jun S, Artandi MK, Shah N, Kim SK, Artandi SE - PLoS Genet. (2007)

Bottom Line: This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood.We show that TERT(ci) retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis.These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Stanford School of Medicine, Stanford, California, United States of America.

ABSTRACT
Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERT(ci)) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERT(ci) retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.

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TERT Regulates a Concerted Transcriptional Program Overlapping Hair Growth and Anti–Hair Growth Genes in Normal Hair Cycling(A) Histogram showing the frequency of genes whose start sites clustered using a randomly generated gene list equal in size to the TERT-regulated gene set (10,000 permutations). TERT-regulated genes reside in 87 clusters (black arrow), whereas only 33 clustered genes are expected.(B) TERT-activated genes are highly enriched with hair growth pattern genes (100 hair growth genes; 1 anti–hair growth gene; 287 others).(C) TERT-repressed genes are highly enriched with anti–hair growth genes (30 anti–hair growth genes; 1 hair growth gene; 206 others).(D–E) ROC plots of various TERT-activated gene lists and TERT-repressed gene lists, generated by different FDR thresholds, in predicting hair growth pattern genes (D) or anti–hair growth pattern genes (E).
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pgen-0040010-g006: TERT Regulates a Concerted Transcriptional Program Overlapping Hair Growth and Anti–Hair Growth Genes in Normal Hair Cycling(A) Histogram showing the frequency of genes whose start sites clustered using a randomly generated gene list equal in size to the TERT-regulated gene set (10,000 permutations). TERT-regulated genes reside in 87 clusters (black arrow), whereas only 33 clustered genes are expected.(B) TERT-activated genes are highly enriched with hair growth pattern genes (100 hair growth genes; 1 anti–hair growth gene; 287 others).(C) TERT-repressed genes are highly enriched with anti–hair growth genes (30 anti–hair growth genes; 1 hair growth gene; 206 others).(D–E) ROC plots of various TERT-activated gene lists and TERT-repressed gene lists, generated by different FDR thresholds, in predicting hair growth pattern genes (D) or anti–hair growth pattern genes (E).

Mentions: We noted that TERT-regulated genes were frequently members of multi-gene families whose transcriptional start sites are in close physical proximity. For example, TERT strongly activated expression of hair keratins, such as Krt31 through Krt36. These genes likely arose through gene duplication and reside in the keratin locus on chromosome 11. It is becoming increasingly recognized that the genomic organization of coordinately regulated genes is non-random and that such genes are often chromosomally clustered in eukaryotes. Examples include genes regulated in a tissue-specific fashion and genes regulated as targets in specific signal transduction pathways [33,34]. Physical clustering of coordinately regulated genes may facilitate the organization of actively transcribed chromatin into specific nuclear domains [35]. To determine if TERT-regulated genes are commonly clustered on chromosomes, we compared the frequency of chromosomal clustering among TERT-regulated genes compared to equal numbers of randomly permuted genes. Among 586 TERT-regulated genes for which transcriptional start sites (TSS) could be assigned, 141 genes (24.1%) were within 100 kb of another gene, resulting in 87 chromosomal clusters (Table S4). Choosing the same number of genes within each chromosome at random and analyzing their TSS proximity for 10,000 iterations resulted in a mean of 33 chromosomal clusters, indicating that TERT-regulated genes were significantly clustered along chromosomes (Figure 6A, and Tables S4 and S5; p < 0.0001). Moreover, TERT-repressed genes were also chromosomally clustered (Table S5; p < 0.0001 for both). The dramatically enhanced clustering of TERT-regulated genes is consistent with TERT controlling a concerted transcriptional program.


TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program.

Choi J, Southworth LK, Sarin KY, Venteicher AS, Ma W, Chang W, Cheung P, Jun S, Artandi MK, Shah N, Kim SK, Artandi SE - PLoS Genet. (2007)

TERT Regulates a Concerted Transcriptional Program Overlapping Hair Growth and Anti–Hair Growth Genes in Normal Hair Cycling(A) Histogram showing the frequency of genes whose start sites clustered using a randomly generated gene list equal in size to the TERT-regulated gene set (10,000 permutations). TERT-regulated genes reside in 87 clusters (black arrow), whereas only 33 clustered genes are expected.(B) TERT-activated genes are highly enriched with hair growth pattern genes (100 hair growth genes; 1 anti–hair growth gene; 287 others).(C) TERT-repressed genes are highly enriched with anti–hair growth genes (30 anti–hair growth genes; 1 hair growth gene; 206 others).(D–E) ROC plots of various TERT-activated gene lists and TERT-repressed gene lists, generated by different FDR thresholds, in predicting hair growth pattern genes (D) or anti–hair growth pattern genes (E).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211538&req=5

pgen-0040010-g006: TERT Regulates a Concerted Transcriptional Program Overlapping Hair Growth and Anti–Hair Growth Genes in Normal Hair Cycling(A) Histogram showing the frequency of genes whose start sites clustered using a randomly generated gene list equal in size to the TERT-regulated gene set (10,000 permutations). TERT-regulated genes reside in 87 clusters (black arrow), whereas only 33 clustered genes are expected.(B) TERT-activated genes are highly enriched with hair growth pattern genes (100 hair growth genes; 1 anti–hair growth gene; 287 others).(C) TERT-repressed genes are highly enriched with anti–hair growth genes (30 anti–hair growth genes; 1 hair growth gene; 206 others).(D–E) ROC plots of various TERT-activated gene lists and TERT-repressed gene lists, generated by different FDR thresholds, in predicting hair growth pattern genes (D) or anti–hair growth pattern genes (E).
Mentions: We noted that TERT-regulated genes were frequently members of multi-gene families whose transcriptional start sites are in close physical proximity. For example, TERT strongly activated expression of hair keratins, such as Krt31 through Krt36. These genes likely arose through gene duplication and reside in the keratin locus on chromosome 11. It is becoming increasingly recognized that the genomic organization of coordinately regulated genes is non-random and that such genes are often chromosomally clustered in eukaryotes. Examples include genes regulated in a tissue-specific fashion and genes regulated as targets in specific signal transduction pathways [33,34]. Physical clustering of coordinately regulated genes may facilitate the organization of actively transcribed chromatin into specific nuclear domains [35]. To determine if TERT-regulated genes are commonly clustered on chromosomes, we compared the frequency of chromosomal clustering among TERT-regulated genes compared to equal numbers of randomly permuted genes. Among 586 TERT-regulated genes for which transcriptional start sites (TSS) could be assigned, 141 genes (24.1%) were within 100 kb of another gene, resulting in 87 chromosomal clusters (Table S4). Choosing the same number of genes within each chromosome at random and analyzing their TSS proximity for 10,000 iterations resulted in a mean of 33 chromosomal clusters, indicating that TERT-regulated genes were significantly clustered along chromosomes (Figure 6A, and Tables S4 and S5; p < 0.0001). Moreover, TERT-repressed genes were also chromosomally clustered (Table S5; p < 0.0001 for both). The dramatically enhanced clustering of TERT-regulated genes is consistent with TERT controlling a concerted transcriptional program.

Bottom Line: This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood.We show that TERT(ci) retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis.These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Stanford School of Medicine, Stanford, California, United States of America.

ABSTRACT
Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERT(ci)) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERT(ci) retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.

Show MeSH
Related in: MedlinePlus