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

Abstract

Cellular plasticity for fate acquisition is associated with distinct chromatin states, which include histone modifications, dynamic association of chromatin factors with the DNA, and global chromatin compaction and nuclear organization. While embryonic stem cell (ESC) plasticity in vitro and its link with chromatin states have been characterized in depth, little is known about tissue stem cell plasticity in vivo, during adult tissue homeostasis. Recently, we reported a distinct globally low level of histone H3 K4/9/27me3 in mouse hair follicle stem cells (HFSCs) during quiescence. This occurred at the stage preceding fate acquisition, when HFSC fate plasticity must be at its highest. This hypomethylated state was required for proper skin homeostasis and timely hair cycle. Here, we show both in the live tissue and in cell culture that at quiescence HFSCs have higher exchange rates for core histone H2B when compared with proliferative or differentiated cells. This denoted a hyperdynamic chromatin state, which was previously associated with high cell fate plasticity in ESCs. Moreover, we find that quiescent HFSCs display a higher propensity for de-differentiation in response to Yamanaka’s reprogramming factors in vivo. These results further support our recent model in which HFSCs render their chromatin into a specific state at quiescence, which is attuned to higher cell fate plasticity.

Stem cell‐intrinsic mechanisms regulating adult hair follicle homeostasis

“…In our recent studies, global reduction of H3 K4/9/27me3 (global hypomethylation) has been shown to occur in quiescent late catagen HFSCs compared to proliferative early anagen HFSCs, suggesting increased HFSC cell plasticity during quiescence, prior to HFSC fate decision for self‐renewal or differentiation 26,128 . Follow‐up in vitro and in vivo experiments further strengthened our model, where quiescent HFSCs were found to have higher chromatin factor exchange rates and increased tendencies to reprogram upon Yamanaka factors exposure, compared to their proliferative counterparts 128 . Data suggest that BMP signalling may be found both upstream and downstream of histone methylation in a negative feedback loop that remains to be directly tested in vivo 26,59 .…”

“…26,128 Follow-up in vitro and in vivo experiments further strengthened our model, where quiescent HFSCs were found to have higher chromatin factor exchange rates and increased tendencies to reprogram upon Yamanaka factors exposure, compared to their proliferative counterparts. 128 Data suggest that BMP signalling may be found both upstream and downstream of histone methylation in a negative feedback loop that remains to be directly tested in vivo. 26,59 Results of our studies demonstrate the importance of histone methylation marks in adult HFSC function and suggest a link with quiescence and fate plasticity during homeostasis and injury repair.…”

“…194 Development of technologies such as SHARE-seq will allow direct probing of chromatin structure in vivo, and permit the field to move to the next level of understanding chromatin structure in the context of epigenetic marks and cell-fate decisions in a living tissue. Chromatin dynamics, and regulation of DNA-bound protein exchange rates, and how this affects HFSC plasticity is also in its infancy 128 and requires more investigation.…”

Histone H3 K4/9/27 Trimethylation Levels Affect Wound Healing and Stem Cell Dynamics in Adult Skin

“…Similar with embryonic SCs, the catagen hypomethylation of HFSCs might allow high plasticity, or flexibility in subsequent SC fate acquisition (Figure 1A). In fact, we found that other measurements of plasticity, such as dynamic exchange of chromatin-bound factors, and reprogramming ability by the Yamanaka 4F factors are also elevated at Catagen (Lee and Tumbar, 2017).…”