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Imprinted genes that regulate early mammalian growth are coexpressed in somatic stem cells.

Berg JS, Lin KK, Sonnet C, Boles NC, Weksberg DC, Nguyen H, Holt LJ, Rickwood D, Daly RJ, Goodell MA - PLoS ONE (2011)

Bottom Line: Here, we scrutinized data comparing genes expressed in murine long-term hematopoietic stem cells with their differentiated counterparts and observed that a disproportionate number were members of the developmentally-important, monoallelically expressed imprinted genes.Studying a subset, which are members of a purported imprinted gene network (IGN), we found their expression in HSCs rapidly altered upon hematopoietic perturbations.The parallel down-regulation of these genes postnatally in response to proliferation and differentiation suggests that the IGN could play a mechanistic role in both cell growth and tissue homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.

ABSTRACT
Lifelong, many somatic tissues are replenished by specialized adult stem cells. These stem cells are generally rare, infrequently dividing, occupy a unique niche, and can rapidly respond to injury to maintain a steady tissue size. Despite these commonalities, few shared regulatory mechanisms have been identified. Here, we scrutinized data comparing genes expressed in murine long-term hematopoietic stem cells with their differentiated counterparts and observed that a disproportionate number were members of the developmentally-important, monoallelically expressed imprinted genes. Studying a subset, which are members of a purported imprinted gene network (IGN), we found their expression in HSCs rapidly altered upon hematopoietic perturbations. These imprinted genes were also predominantly expressed in stem/progenitor cells of the adult epidermis and skeletal muscle in mice, relative to their differentiated counterparts. The parallel down-regulation of these genes postnatally in response to proliferation and differentiation suggests that the IGN could play a mechanistic role in both cell growth and tissue homeostasis.

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IGN expression is retained in mouse and human somatic stem cell populations but not embryonic stem cells.The expression of imprinted genes was compared in (A) human bone marrow CD34+ vs. CD34− cells, (B) mouse whole muscle cells during skeletal muscle maturation from P5 to adulthood, (C) quiescent muscle satellite cells (SCs) vs. whole muscle (non-SCs), and (D) mouse skin stem cells vs. keratinocytes (non stem cells). The data representing at least two independently isolated biological replicates for each population are shown in heat maps representing fold differences in expression compared to the reference sample (yellow). Grey shading represents RT-PCR probes that failed to amplify in either population. (E–G) GSEA of gene expression in three of the cell population comparisons is shown in Table 1. Each example shows enrichment for the imprinted gene set, with an FDR q-value ≤5% and an enrichment P-value≤0.03. EB, embryoid bodies; ESC, embryonic stem cells; HFSCs, hair follicle stem cells. Supplementary information is provided in Figure S1, showing the monoallelic expression nature of genes such as Dlk1, Gtl2, H19, Igf2, and Peg3 in mouse HSCs, as well as Table S2, showing the SNPs used for the analysis of monoalleic expression.
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pone-0026410-g003: IGN expression is retained in mouse and human somatic stem cell populations but not embryonic stem cells.The expression of imprinted genes was compared in (A) human bone marrow CD34+ vs. CD34− cells, (B) mouse whole muscle cells during skeletal muscle maturation from P5 to adulthood, (C) quiescent muscle satellite cells (SCs) vs. whole muscle (non-SCs), and (D) mouse skin stem cells vs. keratinocytes (non stem cells). The data representing at least two independently isolated biological replicates for each population are shown in heat maps representing fold differences in expression compared to the reference sample (yellow). Grey shading represents RT-PCR probes that failed to amplify in either population. (E–G) GSEA of gene expression in three of the cell population comparisons is shown in Table 1. Each example shows enrichment for the imprinted gene set, with an FDR q-value ≤5% and an enrichment P-value≤0.03. EB, embryoid bodies; ESC, embryonic stem cells; HFSCs, hair follicle stem cells. Supplementary information is provided in Figure S1, showing the monoallelic expression nature of genes such as Dlk1, Gtl2, H19, Igf2, and Peg3 in mouse HSCs, as well as Table S2, showing the SNPs used for the analysis of monoalleic expression.

Mentions: The imprinted genes analyzed here represent 10 of the 11 imprinted genes identified in a study that used microarrays to detect genes that were downregulated in murine whole kidney, heart, and lung from birth to maturity [17]. This finding, combined with our data from LT-HSCs, suggests that our group of imprinted genes are broadly expressed in embryonic and rapidly growing postnatal tissues, but then becomes restricted to tissue-specific stem cells, which retain the license to proliferate and differentiate to meet specific organismal demands. To test this concept, we studied additional tissues and stem cells. After confirming selective expression in human CD34+ stem cells from whole bone marrow (Figure 3A) and cord blood (data not shown) we found that all of the 10 genes tested were highly expressed in whole mouse postnatal day-5 (P5) skeletal muscle and were downregulated >100-fold in whole adult (6- to 8-week-old) muscle (Figure 3B). However, each imprinted gene was expressed in muscle satellite cells isolated from either P5 or adult mice with relatively few differences (data not shown). Importantly, except for Peg3, H19, and Gt12, the imprinted genes were expressed at least 10-fold more highly in quiescent satellite cells than in whole muscle (Figure 3C). In skin, 9 of the 10 imprinted genes were detected in epidermal stem cells (CD34+ integrin α6+ keratinocytes), with Cdkn1c, Dlk1, Grb10, Mest, Ndn and Peg3 showing at least 8-fold higher expression levels in stem vs. non-stem cells (Figure 3D). These results clearly demonstrate that the pattern of imprinted gene expression is largely retained in human hematopoietic stem cells, as well as two other murine stem cell compartments. The minor variability of this pattern among different somatic stem cells could be due to cell type-dependent differences in the composition of the proposed regulatory network, or to heterogeneity within the muscle satellite cell and skin stem cell samples (which may represent a mixture of long-term and short-term stem and progenitor cells).


Imprinted genes that regulate early mammalian growth are coexpressed in somatic stem cells.

Berg JS, Lin KK, Sonnet C, Boles NC, Weksberg DC, Nguyen H, Holt LJ, Rickwood D, Daly RJ, Goodell MA - PLoS ONE (2011)

IGN expression is retained in mouse and human somatic stem cell populations but not embryonic stem cells.The expression of imprinted genes was compared in (A) human bone marrow CD34+ vs. CD34− cells, (B) mouse whole muscle cells during skeletal muscle maturation from P5 to adulthood, (C) quiescent muscle satellite cells (SCs) vs. whole muscle (non-SCs), and (D) mouse skin stem cells vs. keratinocytes (non stem cells). The data representing at least two independently isolated biological replicates for each population are shown in heat maps representing fold differences in expression compared to the reference sample (yellow). Grey shading represents RT-PCR probes that failed to amplify in either population. (E–G) GSEA of gene expression in three of the cell population comparisons is shown in Table 1. Each example shows enrichment for the imprinted gene set, with an FDR q-value ≤5% and an enrichment P-value≤0.03. EB, embryoid bodies; ESC, embryonic stem cells; HFSCs, hair follicle stem cells. Supplementary information is provided in Figure S1, showing the monoallelic expression nature of genes such as Dlk1, Gtl2, H19, Igf2, and Peg3 in mouse HSCs, as well as Table S2, showing the SNPs used for the analysis of monoalleic expression.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198398&req=5

pone-0026410-g003: IGN expression is retained in mouse and human somatic stem cell populations but not embryonic stem cells.The expression of imprinted genes was compared in (A) human bone marrow CD34+ vs. CD34− cells, (B) mouse whole muscle cells during skeletal muscle maturation from P5 to adulthood, (C) quiescent muscle satellite cells (SCs) vs. whole muscle (non-SCs), and (D) mouse skin stem cells vs. keratinocytes (non stem cells). The data representing at least two independently isolated biological replicates for each population are shown in heat maps representing fold differences in expression compared to the reference sample (yellow). Grey shading represents RT-PCR probes that failed to amplify in either population. (E–G) GSEA of gene expression in three of the cell population comparisons is shown in Table 1. Each example shows enrichment for the imprinted gene set, with an FDR q-value ≤5% and an enrichment P-value≤0.03. EB, embryoid bodies; ESC, embryonic stem cells; HFSCs, hair follicle stem cells. Supplementary information is provided in Figure S1, showing the monoallelic expression nature of genes such as Dlk1, Gtl2, H19, Igf2, and Peg3 in mouse HSCs, as well as Table S2, showing the SNPs used for the analysis of monoalleic expression.
Mentions: The imprinted genes analyzed here represent 10 of the 11 imprinted genes identified in a study that used microarrays to detect genes that were downregulated in murine whole kidney, heart, and lung from birth to maturity [17]. This finding, combined with our data from LT-HSCs, suggests that our group of imprinted genes are broadly expressed in embryonic and rapidly growing postnatal tissues, but then becomes restricted to tissue-specific stem cells, which retain the license to proliferate and differentiate to meet specific organismal demands. To test this concept, we studied additional tissues and stem cells. After confirming selective expression in human CD34+ stem cells from whole bone marrow (Figure 3A) and cord blood (data not shown) we found that all of the 10 genes tested were highly expressed in whole mouse postnatal day-5 (P5) skeletal muscle and were downregulated >100-fold in whole adult (6- to 8-week-old) muscle (Figure 3B). However, each imprinted gene was expressed in muscle satellite cells isolated from either P5 or adult mice with relatively few differences (data not shown). Importantly, except for Peg3, H19, and Gt12, the imprinted genes were expressed at least 10-fold more highly in quiescent satellite cells than in whole muscle (Figure 3C). In skin, 9 of the 10 imprinted genes were detected in epidermal stem cells (CD34+ integrin α6+ keratinocytes), with Cdkn1c, Dlk1, Grb10, Mest, Ndn and Peg3 showing at least 8-fold higher expression levels in stem vs. non-stem cells (Figure 3D). These results clearly demonstrate that the pattern of imprinted gene expression is largely retained in human hematopoietic stem cells, as well as two other murine stem cell compartments. The minor variability of this pattern among different somatic stem cells could be due to cell type-dependent differences in the composition of the proposed regulatory network, or to heterogeneity within the muscle satellite cell and skin stem cell samples (which may represent a mixture of long-term and short-term stem and progenitor cells).

Bottom Line: Here, we scrutinized data comparing genes expressed in murine long-term hematopoietic stem cells with their differentiated counterparts and observed that a disproportionate number were members of the developmentally-important, monoallelically expressed imprinted genes.Studying a subset, which are members of a purported imprinted gene network (IGN), we found their expression in HSCs rapidly altered upon hematopoietic perturbations.The parallel down-regulation of these genes postnatally in response to proliferation and differentiation suggests that the IGN could play a mechanistic role in both cell growth and tissue homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.

ABSTRACT
Lifelong, many somatic tissues are replenished by specialized adult stem cells. These stem cells are generally rare, infrequently dividing, occupy a unique niche, and can rapidly respond to injury to maintain a steady tissue size. Despite these commonalities, few shared regulatory mechanisms have been identified. Here, we scrutinized data comparing genes expressed in murine long-term hematopoietic stem cells with their differentiated counterparts and observed that a disproportionate number were members of the developmentally-important, monoallelically expressed imprinted genes. Studying a subset, which are members of a purported imprinted gene network (IGN), we found their expression in HSCs rapidly altered upon hematopoietic perturbations. These imprinted genes were also predominantly expressed in stem/progenitor cells of the adult epidermis and skeletal muscle in mice, relative to their differentiated counterparts. The parallel down-regulation of these genes postnatally in response to proliferation and differentiation suggests that the IGN could play a mechanistic role in both cell growth and tissue homeostasis.

Show MeSH
Related in: MedlinePlus