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Comparative computational analysis of pluripotency in human and mouse stem cells.

Ernst M, Abu Dawud R, Kurtz A, Schotta G, Taher L, Fuellen G - Sci Rep (2015)

Bottom Line: Pluripotent cells can be subdivided into two distinct states, the naïve and the primed state, the latter being further advanced on the path of differentiation.Reprogramming of human stem cells into a more naïve-like state is an important research focus.The pipeline consists of identifying regulated start-ups/shut-downs in terms of molecular interactions, followed by functional annotation of the genes involved and aggregation of results across conditions, yielding sets of mechanisms that are consistently regulated in transitions towards similar states of pluripotency.

View Article: PubMed Central - PubMed

Affiliation: Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany.

ABSTRACT
Pluripotent cells can be subdivided into two distinct states, the naïve and the primed state, the latter being further advanced on the path of differentiation. There are substantial differences in the regulation of pluripotency between human and mouse, and in humans only stem cells that resemble the primed state in mouse are readily available. Reprogramming of human stem cells into a more naïve-like state is an important research focus. Here, we developed a pipeline to reanalyze transcriptomics data sets that describe both states, naïve and primed pluripotency, in human and mouse. The pipeline consists of identifying regulated start-ups/shut-downs in terms of molecular interactions, followed by functional annotation of the genes involved and aggregation of results across conditions, yielding sets of mechanisms that are consistently regulated in transitions towards similar states of pluripotency. Our results suggest that one published protocol for naïve human cells gave rise to human cells that indeed share putative mechanisms with the prototypical naïve mouse pluripotent cells, such as DNA damage response and histone acetylation. However, cellular response and differentiation-related mechanisms are similar between the naïve human state and the primed mouse state, so the naïve human state did not fully reflect the naïve mouse state.

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Related in: MedlinePlus

Principal component analysis (PCA) of evidence for associations between comparisons and GOBP terms.PCA was performed on the matrix shown in Figure 4, taking the comparisons as samples and the GOBP terms as variable names. The comparisons are numbered, with the numbers matching those assigned in Figure 3 and Supplementary Table S1. Colours are used to reflect sample membership in the block aggregates naïve and primed, as defined in Figure 3, with grey indicating samples that are in neither aggregate.
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f5: Principal component analysis (PCA) of evidence for associations between comparisons and GOBP terms.PCA was performed on the matrix shown in Figure 4, taking the comparisons as samples and the GOBP terms as variable names. The comparisons are numbered, with the numbers matching those assigned in Figure 3 and Supplementary Table S1. Colours are used to reflect sample membership in the block aggregates naïve and primed, as defined in Figure 3, with grey indicating samples that are in neither aggregate.

Mentions: In the second noise reduction step, the gene sets that we defined for the comparisons in the first step were subjected to a functional analysis based on their GOBP annotation (see Methods). We constructed a heatmap showing enriched and depleted GOBP terms for each of the twelve gene sets corresponding to the twelve comparisons (Figure 4). In contrast to the primed block aggregate, the naïve one features a larger number of depleted GOBP terms. This is also the case for the comparison #1 between NH (source) and NM (target), which thus captures “naïvity” in mouse. This enrichment pattern supports a model in which there is an upregulation of a multitude of pathways in the primed (but not naive) pluripotent stem cells. Next, we subjected the GOBP matrix (Figure 4) to PCA, using the GOBP terms as variable names (Figure 5). The first two PCs explain ~52% and ~14%, respectively, of the total variance. The first PC clearly separates the natural block aggregates primed and naïve, making the distinction between naïve and primed pluripotency the most outstanding feature of our data set.


Comparative computational analysis of pluripotency in human and mouse stem cells.

Ernst M, Abu Dawud R, Kurtz A, Schotta G, Taher L, Fuellen G - Sci Rep (2015)

Principal component analysis (PCA) of evidence for associations between comparisons and GOBP terms.PCA was performed on the matrix shown in Figure 4, taking the comparisons as samples and the GOBP terms as variable names. The comparisons are numbered, with the numbers matching those assigned in Figure 3 and Supplementary Table S1. Colours are used to reflect sample membership in the block aggregates naïve and primed, as defined in Figure 3, with grey indicating samples that are in neither aggregate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4300513&req=5

f5: Principal component analysis (PCA) of evidence for associations between comparisons and GOBP terms.PCA was performed on the matrix shown in Figure 4, taking the comparisons as samples and the GOBP terms as variable names. The comparisons are numbered, with the numbers matching those assigned in Figure 3 and Supplementary Table S1. Colours are used to reflect sample membership in the block aggregates naïve and primed, as defined in Figure 3, with grey indicating samples that are in neither aggregate.
Mentions: In the second noise reduction step, the gene sets that we defined for the comparisons in the first step were subjected to a functional analysis based on their GOBP annotation (see Methods). We constructed a heatmap showing enriched and depleted GOBP terms for each of the twelve gene sets corresponding to the twelve comparisons (Figure 4). In contrast to the primed block aggregate, the naïve one features a larger number of depleted GOBP terms. This is also the case for the comparison #1 between NH (source) and NM (target), which thus captures “naïvity” in mouse. This enrichment pattern supports a model in which there is an upregulation of a multitude of pathways in the primed (but not naive) pluripotent stem cells. Next, we subjected the GOBP matrix (Figure 4) to PCA, using the GOBP terms as variable names (Figure 5). The first two PCs explain ~52% and ~14%, respectively, of the total variance. The first PC clearly separates the natural block aggregates primed and naïve, making the distinction between naïve and primed pluripotency the most outstanding feature of our data set.

Bottom Line: Pluripotent cells can be subdivided into two distinct states, the naïve and the primed state, the latter being further advanced on the path of differentiation.Reprogramming of human stem cells into a more naïve-like state is an important research focus.The pipeline consists of identifying regulated start-ups/shut-downs in terms of molecular interactions, followed by functional annotation of the genes involved and aggregation of results across conditions, yielding sets of mechanisms that are consistently regulated in transitions towards similar states of pluripotency.

View Article: PubMed Central - PubMed

Affiliation: Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany.

ABSTRACT
Pluripotent cells can be subdivided into two distinct states, the naïve and the primed state, the latter being further advanced on the path of differentiation. There are substantial differences in the regulation of pluripotency between human and mouse, and in humans only stem cells that resemble the primed state in mouse are readily available. Reprogramming of human stem cells into a more naïve-like state is an important research focus. Here, we developed a pipeline to reanalyze transcriptomics data sets that describe both states, naïve and primed pluripotency, in human and mouse. The pipeline consists of identifying regulated start-ups/shut-downs in terms of molecular interactions, followed by functional annotation of the genes involved and aggregation of results across conditions, yielding sets of mechanisms that are consistently regulated in transitions towards similar states of pluripotency. Our results suggest that one published protocol for naïve human cells gave rise to human cells that indeed share putative mechanisms with the prototypical naïve mouse pluripotent cells, such as DNA damage response and histone acetylation. However, cellular response and differentiation-related mechanisms are similar between the naïve human state and the primed mouse state, so the naïve human state did not fully reflect the naïve mouse state.

Show MeSH
Related in: MedlinePlus