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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-Regulated Genes Strongly Resemble Myc- and Wnt-Regulated Genes, and Are Enriched with TCF/LEF Binding Sites(A) Representative GSEA results show that Myc and Wnt gene sets are highly enriched in our TERT-regulated dataset. Within each MSigDB gene set, horizontal black bars represent genes matching the rank ordered TERT-regulated dataset. Gene set names are denoted on top of each box and normalized enrichment scores (NES) on bottom. Note that negative NES values indicate enrichment in TERT-activated genes, and positive values indicate enrichment in TERT-repressed genes.(B–C) Graphic representation of cis-regulatory motif enrichment in various groups of genes. TCF/LEF sites were enriched in TERT-activated genes; E2F and Myc binding sites were enriched in hair growth genes (B); and CRE-BP and Myc sites were enriched in anti–hair growth genes (C). Although TCF/LEF sites were not over-represented in the entire collection of hair growth genes, they were significantly enriched in the subset of hair growth genes activated by TERT.
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pgen-0040010-g007: TERT-Regulated Genes Strongly Resemble Myc- and Wnt-Regulated Genes, and Are Enriched with TCF/LEF Binding Sites(A) Representative GSEA results show that Myc and Wnt gene sets are highly enriched in our TERT-regulated dataset. Within each MSigDB gene set, horizontal black bars represent genes matching the rank ordered TERT-regulated dataset. Gene set names are denoted on top of each box and normalized enrichment scores (NES) on bottom. Note that negative NES values indicate enrichment in TERT-activated genes, and positive values indicate enrichment in TERT-repressed genes.(B–C) Graphic representation of cis-regulatory motif enrichment in various groups of genes. TCF/LEF sites were enriched in TERT-activated genes; E2F and Myc binding sites were enriched in hair growth genes (B); and CRE-BP and Myc sites were enriched in anti–hair growth genes (C). Although TCF/LEF sites were not over-represented in the entire collection of hair growth genes, they were significantly enriched in the subset of hair growth genes activated by TERT.

Mentions: Based on these results showing that TERT protein activates epidermal progenitor cells and regulates the expression of chromosomally clustered genes that strongly overlap with those controlling natural hair follicle cycling, we hypothesized that TERT protein is a component of specific developmental pathways. To identify these pathways, we used Gene Set Enrichment Analysis (GSEA), a powerful algorithm that allows a statistical comparison of our TERT-regulated gene dataset with 1134 curated gene sets derived from diverse experiments in the literature [37,38]. This approach requires that we reduce our TERT-regulated gene data set to a rank-ordered list, which is then queried by each individual gene set in the curated database. Strikingly, GSEA comparisons revealed strong connectivity between TERT and two pathways known to regulate progenitor cells, Myc and Wnt (Figure 7A and Table S7).


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-Regulated Genes Strongly Resemble Myc- and Wnt-Regulated Genes, and Are Enriched with TCF/LEF Binding Sites(A) Representative GSEA results show that Myc and Wnt gene sets are highly enriched in our TERT-regulated dataset. Within each MSigDB gene set, horizontal black bars represent genes matching the rank ordered TERT-regulated dataset. Gene set names are denoted on top of each box and normalized enrichment scores (NES) on bottom. Note that negative NES values indicate enrichment in TERT-activated genes, and positive values indicate enrichment in TERT-repressed genes.(B–C) Graphic representation of cis-regulatory motif enrichment in various groups of genes. TCF/LEF sites were enriched in TERT-activated genes; E2F and Myc binding sites were enriched in hair growth genes (B); and CRE-BP and Myc sites were enriched in anti–hair growth genes (C). Although TCF/LEF sites were not over-represented in the entire collection of hair growth genes, they were significantly enriched in the subset of hair growth genes activated by TERT.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211538&req=5

pgen-0040010-g007: TERT-Regulated Genes Strongly Resemble Myc- and Wnt-Regulated Genes, and Are Enriched with TCF/LEF Binding Sites(A) Representative GSEA results show that Myc and Wnt gene sets are highly enriched in our TERT-regulated dataset. Within each MSigDB gene set, horizontal black bars represent genes matching the rank ordered TERT-regulated dataset. Gene set names are denoted on top of each box and normalized enrichment scores (NES) on bottom. Note that negative NES values indicate enrichment in TERT-activated genes, and positive values indicate enrichment in TERT-repressed genes.(B–C) Graphic representation of cis-regulatory motif enrichment in various groups of genes. TCF/LEF sites were enriched in TERT-activated genes; E2F and Myc binding sites were enriched in hair growth genes (B); and CRE-BP and Myc sites were enriched in anti–hair growth genes (C). Although TCF/LEF sites were not over-represented in the entire collection of hair growth genes, they were significantly enriched in the subset of hair growth genes activated by TERT.
Mentions: Based on these results showing that TERT protein activates epidermal progenitor cells and regulates the expression of chromosomally clustered genes that strongly overlap with those controlling natural hair follicle cycling, we hypothesized that TERT protein is a component of specific developmental pathways. To identify these pathways, we used Gene Set Enrichment Analysis (GSEA), a powerful algorithm that allows a statistical comparison of our TERT-regulated gene dataset with 1134 curated gene sets derived from diverse experiments in the literature [37,38]. This approach requires that we reduce our TERT-regulated gene data set to a rank-ordered list, which is then queried by each individual gene set in the curated database. Strikingly, GSEA comparisons revealed strong connectivity between TERT and two pathways known to regulate progenitor cells, Myc and Wnt (Figure 7A and Table S7).

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