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

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.

Linking chromatin dynamics, cell fate plasticity, and tissue homeostasis in adult mouse hair follicle stem cells

“…Intriguingly, these data are in line with the data from cultured ESCs (1) where ESCs, compared to more lineage-restricted cell types, showed the highest exchange rates of histone proteins. Moreover, these data agree with our previous report, in which quiescent HFSCs have been shown to have globally reduced histone epigenetic marks (9), another chromatin feature associated with higher plasticity in ESCs and T cell progenitors (10, 11). …”

“…Hypomethylation of H3 K9/27me3 has been previously associated with increased cell fate plasticity in ESCs and in quiescent T-cells in vitro (10, 11). We found that this specialized chromatin state accompanies differential regulation of multiple histone methylases and demethylases, and is associated with BMP signaling (9), previously shown to be critical for proper maintenance of quiescent state (12). Moreover, blocking the establishment of hypomethylation at catagen via chemical inhibition of H3 K4/9/27 methylases led to a pronounced delay in anagen onset.…”

“…Therefore, HFSCs most naïve cell fate state is at catagen, during the stem cell positioning phase. Intriguingly, we have recently shown that bulge cells in catagen display distinct genome-wide hypomethylation of several histone modifications (H3 K4/9/27me3) (9). Hypomethylation of H3 K9/27me3 has been previously associated with increased cell fate plasticity in ESCs and in quiescent T-cells in vitro (10, 11).…”

“…In addition, quiescent HFSCs seem to be more readily de-differentiated, suggesting that these cells may bear higher plasticity than that of proliferative HFSCs. Furthermore, our previous work showed that quiescent HFSCs actively maintain globally low histone methylation status, and inhibition of demethylating enzymes perturbed the subsequent activation (9). Taken together, these data suggest a model where the chromatin of quiescent HFSCs is actively maintained in a more dynamic state that conforms with higher plasticity.…”

Epigenetic control in skin development, homeostasis and injury repair

“…Further in vitro studies showed that Jmjd3 (H3K27me3 demethylase) activation leads to premature epidermis differentiation, whereas Jmjd3 depletion failed to activate epidermal differentiation genes in human keratinocytes . In the bulge, we found that Ezh2 mRNA is downregulated at catagen, whereas Ezh1 remains expressed . Intriguingly, a small subset of genes acquires H3K27me3 marks at catagen, as demonstrated by our Chip‐Seq analysis .…”