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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

Correlation of histone marks and gene expression between EA- and LC-HFSCs.(a–d) PD25 (EA-HFSCs, self-renewing stage) and PD42 (LC-HFSCs, prior to fate decisions) expression arrays were compared with identified groups of genes that behave similarly in their expression across populations and hair cycle stages (see the Methods for acquisition of array and ChIP-seq signals). Fold changes between EA-HFSCs and LC-HFSCs (LC-HFSCs/EA-HFSCs) in array and ChIP-seq signals were log2 transformed, followed by conversion of data matrix into a density plot using R. Genes that were absent with array or ChIP-seq signals were omitted in the plot. Majority of the gene sets analysed showed reduction of H3K27me3 and H3K9me3, regardless of their expression patterns. H3K4me3 levels are relatively less dramatically changed. Interestingly, GUB uniquely show increased level of H3K27me3 from anagen bulge to catagen bulge, suggesting they are under special regulation. These data suggest that the change in gene expression as defined by mRNA levels does not necessarily correlate with the change in histone modification levels. Refer to Supplementary Data 2 for a complete list of ChIP and array signals.
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f5: Correlation of histone marks and gene expression between EA- and LC-HFSCs.(a–d) PD25 (EA-HFSCs, self-renewing stage) and PD42 (LC-HFSCs, prior to fate decisions) expression arrays were compared with identified groups of genes that behave similarly in their expression across populations and hair cycle stages (see the Methods for acquisition of array and ChIP-seq signals). Fold changes between EA-HFSCs and LC-HFSCs (LC-HFSCs/EA-HFSCs) in array and ChIP-seq signals were log2 transformed, followed by conversion of data matrix into a density plot using R. Genes that were absent with array or ChIP-seq signals were omitted in the plot. Majority of the gene sets analysed showed reduction of H3K27me3 and H3K9me3, regardless of their expression patterns. H3K4me3 levels are relatively less dramatically changed. Interestingly, GUB uniquely show increased level of H3K27me3 from anagen bulge to catagen bulge, suggesting they are under special regulation. These data suggest that the change in gene expression as defined by mRNA levels does not necessarily correlate with the change in histone modification levels. Refer to Supplementary Data 2 for a complete list of ChIP and array signals.

Mentions: Next, we asked if subsets of genes that we pre-define based on function, might be differentially methylated at the HFSCs transition to quiescence. General histone H3 K4/K9/K27me3 decrease at TSS in LC-HFSCs relative to EA-HFSCs was detectable in all functionally defined gene sets analysed (Figs 4b and 5a–d, and Supplementary Data 2), with two notable exceptions. First, a relatively large fraction of Genes Upregulated at the mRNA level at all hair cycle stages in the Bulge (GUB) showed elevated H3K27me3 mark in LC-HFSCs (Figs 4b and 5a, arrow), whereas all other gene sets showed reduced H3K27me3 levels. Second, a set of genes previously defined as cell cycle regulators and skin tumour suppressors did not show a decrease of H3K4me3 level at the TSS in LC-HFSCs, like all the other gene sets did, and displayed a striking and atypical lack of H3K27me3 in both LC-HFSCs and EA-HFSCs (Fig. 4b,c, and Supplementary Data 2). These data show that most TSSs lose their histone marks to some degree in LC-HFSCs, and this is irrespective of the mRNA level changes. This loss is most pronounced for H3K9me3, and least pronounced for H3K4me3, whereas H3K27me3 show intermediate decrease and special behaviour at specific gene sets, suggesting these are under specific regulation. These data suggest that the level of H3 K4/K9/K27me3 does not dictate mRNA levels in quiescent HFSCs at catagen.


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)

Correlation of histone marks and gene expression between EA- and LC-HFSCs.(a–d) PD25 (EA-HFSCs, self-renewing stage) and PD42 (LC-HFSCs, prior to fate decisions) expression arrays were compared with identified groups of genes that behave similarly in their expression across populations and hair cycle stages (see the Methods for acquisition of array and ChIP-seq signals). Fold changes between EA-HFSCs and LC-HFSCs (LC-HFSCs/EA-HFSCs) in array and ChIP-seq signals were log2 transformed, followed by conversion of data matrix into a density plot using R. Genes that were absent with array or ChIP-seq signals were omitted in the plot. Majority of the gene sets analysed showed reduction of H3K27me3 and H3K9me3, regardless of their expression patterns. H3K4me3 levels are relatively less dramatically changed. Interestingly, GUB uniquely show increased level of H3K27me3 from anagen bulge to catagen bulge, suggesting they are under special regulation. These data suggest that the change in gene expression as defined by mRNA levels does not necessarily correlate with the change in histone modification levels. Refer to Supplementary Data 2 for a complete list of ChIP and array signals.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Correlation of histone marks and gene expression between EA- and LC-HFSCs.(a–d) PD25 (EA-HFSCs, self-renewing stage) and PD42 (LC-HFSCs, prior to fate decisions) expression arrays were compared with identified groups of genes that behave similarly in their expression across populations and hair cycle stages (see the Methods for acquisition of array and ChIP-seq signals). Fold changes between EA-HFSCs and LC-HFSCs (LC-HFSCs/EA-HFSCs) in array and ChIP-seq signals were log2 transformed, followed by conversion of data matrix into a density plot using R. Genes that were absent with array or ChIP-seq signals were omitted in the plot. Majority of the gene sets analysed showed reduction of H3K27me3 and H3K9me3, regardless of their expression patterns. H3K4me3 levels are relatively less dramatically changed. Interestingly, GUB uniquely show increased level of H3K27me3 from anagen bulge to catagen bulge, suggesting they are under special regulation. These data suggest that the change in gene expression as defined by mRNA levels does not necessarily correlate with the change in histone modification levels. Refer to Supplementary Data 2 for a complete list of ChIP and array signals.
Mentions: Next, we asked if subsets of genes that we pre-define based on function, might be differentially methylated at the HFSCs transition to quiescence. General histone H3 K4/K9/K27me3 decrease at TSS in LC-HFSCs relative to EA-HFSCs was detectable in all functionally defined gene sets analysed (Figs 4b and 5a–d, and Supplementary Data 2), with two notable exceptions. First, a relatively large fraction of Genes Upregulated at the mRNA level at all hair cycle stages in the Bulge (GUB) showed elevated H3K27me3 mark in LC-HFSCs (Figs 4b and 5a, arrow), whereas all other gene sets showed reduced H3K27me3 levels. Second, a set of genes previously defined as cell cycle regulators and skin tumour suppressors did not show a decrease of H3K4me3 level at the TSS in LC-HFSCs, like all the other gene sets did, and displayed a striking and atypical lack of H3K27me3 in both LC-HFSCs and EA-HFSCs (Fig. 4b,c, and Supplementary Data 2). These data show that most TSSs lose their histone marks to some degree in LC-HFSCs, and this is irrespective of the mRNA level changes. This loss is most pronounced for H3K9me3, and least pronounced for H3K4me3, whereas H3K27me3 show intermediate decrease and special behaviour at specific gene sets, suggesting these are under specific regulation. These data suggest that the level of H3 K4/K9/K27me3 does not dictate mRNA levels in quiescent HFSCs at catagen.

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