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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

Reduction of H3 K4/K9/K27me3 at functional genomic regions at catagen.(a) List of all genomic regions covered by MACS peaks from three marks in all four populations. (b) Box whisker plot of genomic enrichment of histone marks in EA-HFSCs (red) and LC-HFSCs (blue). Number of reads was normalized to 1 million of total mapped reads (normalized tag density). Note that the individual histone marks are higher at expected regulatory sites relative to the rest of the genome (for example, enrichment of H3K4me3 in TSS/promoters, H3K27me3 in intergenic and H3K9me3 in satellite regions), yet display overall decrease compared with EA-HFSCs. See the Methods for detail. (c) Average sum of all tag densities of H3K4me3 in all chromosomal loci analysed. Note that the overall peak intensity is lower by ∼2-fold in LC-HFSCs. (d) Average distribution of H3K4me3 (left panel) and H3K27me3 (right panel) in transcription start sites (TSS) of EA-HFSCs (red) and LC-HFSCs (blue) and (e) all three marks in transcription termination sites (TTS; right panel). Note the clear reduction of marks in LC-HFSCs. (f–h) Quantitative heat plot analysis of H3K4me3 (K4), H3K27me3 (K27) and H3K9me3 (K9) levels on TSS (f), simple repeats (g) or satellite regions (h). Notice the reduction of marks in LC-HFSCs highlighted in red (arrow versus arrowheads). UTR, untranslated region; LINE, Long Interspersed Nuclear Element; SINE: Short Interspersed Elements; LTR, Long Terminal Repeats.
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f3: Reduction of H3 K4/K9/K27me3 at functional genomic regions at catagen.(a) List of all genomic regions covered by MACS peaks from three marks in all four populations. (b) Box whisker plot of genomic enrichment of histone marks in EA-HFSCs (red) and LC-HFSCs (blue). Number of reads was normalized to 1 million of total mapped reads (normalized tag density). Note that the individual histone marks are higher at expected regulatory sites relative to the rest of the genome (for example, enrichment of H3K4me3 in TSS/promoters, H3K27me3 in intergenic and H3K9me3 in satellite regions), yet display overall decrease compared with EA-HFSCs. See the Methods for detail. (c) Average sum of all tag densities of H3K4me3 in all chromosomal loci analysed. Note that the overall peak intensity is lower by ∼2-fold in LC-HFSCs. (d) Average distribution of H3K4me3 (left panel) and H3K27me3 (right panel) in transcription start sites (TSS) of EA-HFSCs (red) and LC-HFSCs (blue) and (e) all three marks in transcription termination sites (TTS; right panel). Note the clear reduction of marks in LC-HFSCs. (f–h) Quantitative heat plot analysis of H3K4me3 (K4), H3K27me3 (K27) and H3K9me3 (K9) levels on TSS (f), simple repeats (g) or satellite regions (h). Notice the reduction of marks in LC-HFSCs highlighted in red (arrow versus arrowheads). UTR, untranslated region; LINE, Long Interspersed Nuclear Element; SINE: Short Interspersed Elements; LTR, Long Terminal Repeats.

Mentions: For this, we adapted an existing sequencing data analysis pipeline that allows direct comparisons of fold changes at defined chromosomal loci across samples (see the Methods for details). We defined 201,177 chromosomal loci (Fig. 3a), in which at least one of the three marks was detected as a ‘peak' (via MACS, model-based analysis of ChIP-Seq24) in any one of our populations. We then quantified the signal as ‘normalized tag density' (number of sequencing reads mapped within a specific region per total number of mapped reads normalized across analysed samples; see the Methods for details). As expected for these marks, this analysis revealed enrichment of H3K4me3 at transcription start sites (TSS), 5′ untranslated region and CpG sites, whereas H3K27me3 and H3K9me3 were enriched in regions elsewhere, such as repetitive satellite regions (Fig. 3b).


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)

Reduction of H3 K4/K9/K27me3 at functional genomic regions at catagen.(a) List of all genomic regions covered by MACS peaks from three marks in all four populations. (b) Box whisker plot of genomic enrichment of histone marks in EA-HFSCs (red) and LC-HFSCs (blue). Number of reads was normalized to 1 million of total mapped reads (normalized tag density). Note that the individual histone marks are higher at expected regulatory sites relative to the rest of the genome (for example, enrichment of H3K4me3 in TSS/promoters, H3K27me3 in intergenic and H3K9me3 in satellite regions), yet display overall decrease compared with EA-HFSCs. See the Methods for detail. (c) Average sum of all tag densities of H3K4me3 in all chromosomal loci analysed. Note that the overall peak intensity is lower by ∼2-fold in LC-HFSCs. (d) Average distribution of H3K4me3 (left panel) and H3K27me3 (right panel) in transcription start sites (TSS) of EA-HFSCs (red) and LC-HFSCs (blue) and (e) all three marks in transcription termination sites (TTS; right panel). Note the clear reduction of marks in LC-HFSCs. (f–h) Quantitative heat plot analysis of H3K4me3 (K4), H3K27me3 (K27) and H3K9me3 (K9) levels on TSS (f), simple repeats (g) or satellite regions (h). Notice the reduction of marks in LC-HFSCs highlighted in red (arrow versus arrowheads). UTR, untranslated region; LINE, Long Interspersed Nuclear Element; SINE: Short Interspersed Elements; LTR, Long Terminal Repeats.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Reduction of H3 K4/K9/K27me3 at functional genomic regions at catagen.(a) List of all genomic regions covered by MACS peaks from three marks in all four populations. (b) Box whisker plot of genomic enrichment of histone marks in EA-HFSCs (red) and LC-HFSCs (blue). Number of reads was normalized to 1 million of total mapped reads (normalized tag density). Note that the individual histone marks are higher at expected regulatory sites relative to the rest of the genome (for example, enrichment of H3K4me3 in TSS/promoters, H3K27me3 in intergenic and H3K9me3 in satellite regions), yet display overall decrease compared with EA-HFSCs. See the Methods for detail. (c) Average sum of all tag densities of H3K4me3 in all chromosomal loci analysed. Note that the overall peak intensity is lower by ∼2-fold in LC-HFSCs. (d) Average distribution of H3K4me3 (left panel) and H3K27me3 (right panel) in transcription start sites (TSS) of EA-HFSCs (red) and LC-HFSCs (blue) and (e) all three marks in transcription termination sites (TTS; right panel). Note the clear reduction of marks in LC-HFSCs. (f–h) Quantitative heat plot analysis of H3K4me3 (K4), H3K27me3 (K27) and H3K9me3 (K9) levels on TSS (f), simple repeats (g) or satellite regions (h). Notice the reduction of marks in LC-HFSCs highlighted in red (arrow versus arrowheads). UTR, untranslated region; LINE, Long Interspersed Nuclear Element; SINE: Short Interspersed Elements; LTR, Long Terminal Repeats.
Mentions: For this, we adapted an existing sequencing data analysis pipeline that allows direct comparisons of fold changes at defined chromosomal loci across samples (see the Methods for details). We defined 201,177 chromosomal loci (Fig. 3a), in which at least one of the three marks was detected as a ‘peak' (via MACS, model-based analysis of ChIP-Seq24) in any one of our populations. We then quantified the signal as ‘normalized tag density' (number of sequencing reads mapped within a specific region per total number of mapped reads normalized across analysed samples; see the Methods for details). As expected for these marks, this analysis revealed enrichment of H3K4me3 at transcription start sites (TSS), 5′ untranslated region and CpG sites, whereas H3K27me3 and H3K9me3 were enriched in regions elsewhere, such as repetitive satellite regions (Fig. 3b).

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