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Signalling couples hair follicle stem cell quiescence with reduced histone H3 K4/K9/K27me3 for proper tissue homeostasis.

Lee J, Kang S, Lilja KC, Colletier KJ, Scheitz CJ, Zhang YV, Tumbar T - Nat Commun (2016)

Bottom Line: The level of marks over specific gene promoters did not correlate to mRNA level changes in quiescent HFSCs.Furthermore, removal of proliferation factors and addition of BMP4 reduced histone methylases and increased demethylases mRNAs in cultured skin epithelial cells.We conclude that signalling couples hair follicle stem cell quiescence with reduced H3 K4/K9/K27me3 levels for proper tissue homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA.

ABSTRACT
Mechanisms of plasticity to acquire different cell fates are critical for adult stem cell (SC) potential, yet are poorly understood. Reduced global histone methylation is an epigenetic state known to mediate plasticity in cultured embryonic SCs and T-cell progenitors. Here we find histone H3 K4/K9/K27me3 levels actively reduced in adult mouse skin and hair follicle stem cells (HFSCs) during G0 quiescence. The level of marks over specific gene promoters did not correlate to mRNA level changes in quiescent HFSCs. Skin hypomethylation during quiescence was necessary for subsequent progression of hair homeostasis (cycle). Inhibiting BMP signal, a known HFSC anti-proliferative factor, elevated HFSC methylation in vivo during quiescence prior to proliferation onset. Furthermore, removal of proliferation factors and addition of BMP4 reduced histone methylases and increased demethylases mRNAs in cultured skin epithelial cells. We conclude that signalling couples hair follicle stem cell quiescence with reduced H3 K4/K9/K27me3 levels for proper tissue homeostasis.

No MeSH data available.


Related in: MedlinePlus

Model for signalling coupled regulation of chromatin state and genome plasticity.Hair follicles undergo dramatic remodelling at catagen as they prepare for new growth in the next hair cycle. Hair follicle stem cells at this stage are faced with a bidirectional cell fate choice to (i) remain as a stem cell in the bulge and self-renew at anagen or (ii) migrate out from their niche before division and eventually become a progenitor matrix cell that fuel the hair growth162021. Signalling (that is, BMP) that plays a crucial role in regulating quiescence of hair follicle stem cells14, also may control the level of multiple histone-modifying enzymes, leading to a global reduction of several key histone modification marks previously implicated in transcriptional activation or repression. Such global reduction in histone marks may place the quiescent hair follicle stem cell epigenome at a ‘blank' (or a plastic) state. This would subsequently allow efficient re-writing of the methylation marks throughout the genome in the pattern required to enforce the ultimate cell fate choice. The latter is dictated by the ultimate position within the niche in which the quiescent stem cell finds itself at the onset of hair growth.
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f9: Model for signalling coupled regulation of chromatin state and genome plasticity.Hair follicles undergo dramatic remodelling at catagen as they prepare for new growth in the next hair cycle. Hair follicle stem cells at this stage are faced with a bidirectional cell fate choice to (i) remain as a stem cell in the bulge and self-renew at anagen or (ii) migrate out from their niche before division and eventually become a progenitor matrix cell that fuel the hair growth162021. Signalling (that is, BMP) that plays a crucial role in regulating quiescence of hair follicle stem cells14, also may control the level of multiple histone-modifying enzymes, leading to a global reduction of several key histone modification marks previously implicated in transcriptional activation or repression. Such global reduction in histone marks may place the quiescent hair follicle stem cell epigenome at a ‘blank' (or a plastic) state. This would subsequently allow efficient re-writing of the methylation marks throughout the genome in the pattern required to enforce the ultimate cell fate choice. The latter is dictated by the ultimate position within the niche in which the quiescent stem cell finds itself at the onset of hair growth.

Mentions: Our data suggest that quiescent HFSCs display chromatin features previously associated with high plasticity and low epigenetic identity in ESCs and in quiescent T-cell progenitors211. These are characterized by low levels of histone H3 K4/K9/K27me3 in HFSCs at catagen. Suggestively, this state occurs at the stage during hair homeostasis when quiescent HFSCs are most naïve with respect to fate choice and are preparing for subsequent decisions to either differentiate or self-renew (Fig. 9). Strikingly, the global decrease in levels of histone H3 K4/K9/K27me3 we found at this stage did not affect the mRNA levels in the expected direction. One possible explanation is that steady-state mRNA levels detectable by microarrays are not an accurate reflection of active transcription, and that at catagen mRNA levels are determined by post-transcriptional regulation. Another possibility is that in quiescence (in the absence of cell division) methylation level does not have a direct impact on ongoing or active transcription. Methylation impact on transcription can occur not only by change in binding of transcription factors at functional elements, but also at the large-scale chromatin level. For instance, physical association in trans of genes with large heterochromatic structures (associated with high level of H3K9me3) could broadly enforce gene repression1132. Genome-wide changes in histone methylation levels suggest that regulation at the large-scale chromatin level may be present in the hair follicle homeostasis.


Signalling couples hair follicle stem cell quiescence with reduced histone H3 K4/K9/K27me3 for proper tissue homeostasis.

Lee J, Kang S, Lilja KC, Colletier KJ, Scheitz CJ, Zhang YV, Tumbar T - Nat Commun (2016)

Model for signalling coupled regulation of chromatin state and genome plasticity.Hair follicles undergo dramatic remodelling at catagen as they prepare for new growth in the next hair cycle. Hair follicle stem cells at this stage are faced with a bidirectional cell fate choice to (i) remain as a stem cell in the bulge and self-renew at anagen or (ii) migrate out from their niche before division and eventually become a progenitor matrix cell that fuel the hair growth162021. Signalling (that is, BMP) that plays a crucial role in regulating quiescence of hair follicle stem cells14, also may control the level of multiple histone-modifying enzymes, leading to a global reduction of several key histone modification marks previously implicated in transcriptional activation or repression. Such global reduction in histone marks may place the quiescent hair follicle stem cell epigenome at a ‘blank' (or a plastic) state. This would subsequently allow efficient re-writing of the methylation marks throughout the genome in the pattern required to enforce the ultimate cell fate choice. The latter is dictated by the ultimate position within the niche in which the quiescent stem cell finds itself at the onset of hair growth.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835553&req=5

f9: Model for signalling coupled regulation of chromatin state and genome plasticity.Hair follicles undergo dramatic remodelling at catagen as they prepare for new growth in the next hair cycle. Hair follicle stem cells at this stage are faced with a bidirectional cell fate choice to (i) remain as a stem cell in the bulge and self-renew at anagen or (ii) migrate out from their niche before division and eventually become a progenitor matrix cell that fuel the hair growth162021. Signalling (that is, BMP) that plays a crucial role in regulating quiescence of hair follicle stem cells14, also may control the level of multiple histone-modifying enzymes, leading to a global reduction of several key histone modification marks previously implicated in transcriptional activation or repression. Such global reduction in histone marks may place the quiescent hair follicle stem cell epigenome at a ‘blank' (or a plastic) state. This would subsequently allow efficient re-writing of the methylation marks throughout the genome in the pattern required to enforce the ultimate cell fate choice. The latter is dictated by the ultimate position within the niche in which the quiescent stem cell finds itself at the onset of hair growth.
Mentions: Our data suggest that quiescent HFSCs display chromatin features previously associated with high plasticity and low epigenetic identity in ESCs and in quiescent T-cell progenitors211. These are characterized by low levels of histone H3 K4/K9/K27me3 in HFSCs at catagen. Suggestively, this state occurs at the stage during hair homeostasis when quiescent HFSCs are most naïve with respect to fate choice and are preparing for subsequent decisions to either differentiate or self-renew (Fig. 9). Strikingly, the global decrease in levels of histone H3 K4/K9/K27me3 we found at this stage did not affect the mRNA levels in the expected direction. One possible explanation is that steady-state mRNA levels detectable by microarrays are not an accurate reflection of active transcription, and that at catagen mRNA levels are determined by post-transcriptional regulation. Another possibility is that in quiescence (in the absence of cell division) methylation level does not have a direct impact on ongoing or active transcription. Methylation impact on transcription can occur not only by change in binding of transcription factors at functional elements, but also at the large-scale chromatin level. For instance, physical association in trans of genes with large heterochromatic structures (associated with high level of H3K9me3) could broadly enforce gene repression1132. Genome-wide changes in histone methylation levels suggest that regulation at the large-scale chromatin level may be present in the hair follicle homeostasis.

Bottom Line: The level of marks over specific gene promoters did not correlate to mRNA level changes in quiescent HFSCs.Furthermore, removal of proliferation factors and addition of BMP4 reduced histone methylases and increased demethylases mRNAs in cultured skin epithelial cells.We conclude that signalling couples hair follicle stem cell quiescence with reduced H3 K4/K9/K27me3 levels for proper tissue homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA.

ABSTRACT
Mechanisms of plasticity to acquire different cell fates are critical for adult stem cell (SC) potential, yet are poorly understood. Reduced global histone methylation is an epigenetic state known to mediate plasticity in cultured embryonic SCs and T-cell progenitors. Here we find histone H3 K4/K9/K27me3 levels actively reduced in adult mouse skin and hair follicle stem cells (HFSCs) during G0 quiescence. The level of marks over specific gene promoters did not correlate to mRNA level changes in quiescent HFSCs. Skin hypomethylation during quiescence was necessary for subsequent progression of hair homeostasis (cycle). Inhibiting BMP signal, a known HFSC anti-proliferative factor, elevated HFSC methylation in vivo during quiescence prior to proliferation onset. Furthermore, removal of proliferation factors and addition of BMP4 reduced histone methylases and increased demethylases mRNAs in cultured skin epithelial cells. We conclude that signalling couples hair follicle stem cell quiescence with reduced H3 K4/K9/K27me3 levels for proper tissue homeostasis.

No MeSH data available.


Related in: MedlinePlus