Cell‐type‐ and cell‐state‐specific patterns of covalent modifications on DNA and histone tails form global epigenetic profiles that enable spatiotemporal regulation of gene expression. These epigenetic profiles arise from coordinated activities of transcription factors and epigenetic modifiers, which result in cell‐type‐specific outputs in response to dynamic environmental conditions and signalling pathways. Recent mouse genetic and functional studies have highlighted the physiological significance of global DNA and histone epigenetic modifications in skin. Importantly, specific epigenetic profiles are emerging for adult skin stem cells that are associated with their cell fate plasticity and proper activity in tissue regeneration. We can now begin to draw a more comprehensive picture of how epigenetic modifiers orchestrate their cell‐intrinsic role with microenvironmental cues for proper skin development, homeostasis and wound repair. The field is ripe to begin to implement these findings from the laboratory into skin therapies.
Hair follicle (HF) stem cells (SCs) reside in the bulge region of the hair follicle, 1-3 which is located at the lower permanent portion of HF from which the temporary portion, known as the bulb, periodically emerges. Coordinated activity between the HFSCs and surrounding microenvironment drives the cyclic regeneration of the HF bulb through various phases: growth (anagen), regression (catagen) and quiescence (telogen). 4,5 During early and mid-anagen phase,
Adulte interfollicular epidermis (IFE) renewal is likely orchestrated by physiological demands of its complex tissue architecture comprising spatial and cellular heterogeneity. Mouse tail and back skin display two kinds of basal IFE spatial domains that regenerate at different rates. Here, we elucidate the molecular and cellular states of basal IFE domains by marker expression and single-cell transcriptomics in mouse and human skin. We uncover two paths of basal cell differentiation that in part reflect the IFE spatial domain organization. We unravel previously unrecognized similarities between mouse tail IFE basal domains defined as scales and interscales versus human rete ridges and inter-ridges, respectively. Furthermore, our basal IFE transcriptomics and gene targeting in mice provide evidence supporting a physiological role of IFE domains in adaptation to differential UV exposure. We identify Sox6 as a novel UV-induced and interscale/inter-ridge preferred basal IFE-domain transcription factor, important for IFE proliferation and survival. The spatial, cellular, and molecular organization of IFE basal domains underscores skin adaptation to environmental exposure and its unusual robustness in adult homeostasis.
Secretory phospholipase A 2 Group-IIA (sPLA 2 -IIA) catalyzes the hydrolysis of the sn-2 position of glycerophospholipids to yield fatty acids and lysophospholipids. sPLA 2 -IIA is deregulated in various cancers; however, its role in hair follicle stem cell (HFSC) regulation is obscure. Here we report a transgenic mice overexpressing sPLA 2 -IIA (K14-sPLA 2 -IIA) showed depletion of HFSC pool. This was accompanied with increased differentiation, loss of ortho-parakeratotic organization and enlargement of sebaceous gland, infundibulum and junctional zone. The colony forming efficiency of keratinocytes was significantly reduced. Microarray profiling of HFSCs revealed enhanced level of epithelial mitogens and transcription factors, c-Jun and FosB that may be involved in proliferation and differentiation. Moreover, K14-sPLA 2 -IIA keratinocytes showed enhanced activation of EGFR and JNK1/2 that led to c-Jun activation, which co-related with enhanced differentiation. Further, depletion of stem cells in bulge is associated with high levels of chromatin silencing mark, H3K27me3 and low levels of an activator mark, H3K9ac suggestive of alteration in gene expression contributing toward stem cells differentiation. Our results, first time uncovered that overexpression of sPLA 2 -IIA lead to depletion of HFSCs and differentiation associated with altered histone modification. Thus involvement of sPLA 2 -IIA in stem cells regulation and disease pathogenesis suggest its prospective clinical implications. STEM CELLS
Background: Tissue stem cells (SCs) and cancer cells proliferation is regulated by many common signalling mechanisms. These mechanisms temporally balance proliferation and differentiation events during normal tissue homeostasis and repair. However, the effect of these aberrant signalling mechanisms on the ultimate fate of SCs and cancer cells remains obscure. Methods: To evaluate the functional effects of Secretory Phospholipase A 2-IIA (sPLA 2-IIA) induced abnormal signalling on normal SCs and cancer cells, we have used K14-sPLA 2-IIA transgenic mice hair follicle stem cells (HFSCs), DMBA/TPA induced mouse skin tumour tissues, human oral squamous cell carcinoma (OSCC) and skin squamous cell carcinoma (SCC) derived cell lines. Findings: Our study demonstrates that sPLA 2-IIA induces rapid proliferation of HFSCs, thereby altering the proliferation dynamics leading to a complete loss of the slow cycling H2BGFP positive HFSCs. Interestingly, in vivo reversion study by JNK inhibition exhibited a significant delay in post depilation hair growth, confirming that sPLA 2-IIA promotes HFSCs proliferation through JNK/c-Jun signalling. In a different cellular context, we showed increased expression of sPLA 2-IIA in human OSCC and mouse skin cancer tissues. Importantly, a xenograft of sPLA 2-IIA knockdown cells of OSCC and SCC cell lines showed a concomitant reduction of tumour volume in NOD-SCID mice and decreased JNK/c-Jun signalling. Interpretation: This study unravels how an increased proliferation induced by a common proliferation inducer (sPLA 2-IIA) alters the fate of normal SCs and cancer cells distinctively through common JNK/c-Jun signalling. Thus, sPLA 2-IIA can be a potential target for various diseases including cancer. Fund: This work was partly supported by the Indian Council of Medical Research (ICMR-3097) and ACTREC (42) grants.
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