Abstract
Maintenance of high-turnover tissues such as the epidermis requires a balance between stem cell proliferation and differentiation. The molecular mechanisms governing this process are an area of investigation. Here we show that HNRNPK, a multifunctional protein, is necessary to prevent premature differentiation and sustains the proliferative capacity of epidermal stem and progenitor cells. To prevent premature differentiation of progenitor cells, HNRNPK is necessary for DDX6 to bind a subset of mRNAs that code for transcription factors that promote differentiation. Upon binding, these mRNAs such as GRHL3, KLF4, and ZNF750 are degraded through the mRNA degradation pathway, which prevents premature differentiation. To sustain the proliferative capacity of the epidermis, HNRNPK is necessary for RNA Polymerase II binding to proliferation/self-renewal genes such as MYC, CYR61, FGFBP1, EGFR, and cyclins to promote their expression. Our study establishes a prominent role for HNRNPK in maintaining adult tissue self-renewal through both transcriptional and post-transcriptional mechanisms.
Highlights
Maintenance of high-turnover tissues such as the epidermis requires a balance between stem cell proliferation and differentiation
We show that heterogeneous nuclear ribonucleoprotein K (HNRNPK) prevents premature differentiation of human epidermal progenitor cells by degrading mRNAs coding for differentiation promoting transcription factors through the DDX6 pathway
We previously showed that knockdown of DDX6 in epidermal progenitor cells led to increased KLF4 mRNA stability and expression[14]
Summary
We previously showed that knockdown of DDX6 in epidermal progenitor cells led to increased KLF4 mRNA stability and expression[14]. HNRNPK knockdown cells prematurely differentiated with increased levels of differentiation specific genes many of which have been implicated in skin diseases including KRT1, KRT10, FLG, and LOR (Fig. 1c and Supplementary Fig. 1f)[27,28,29,30]. The mRNAs levels (KLF4, ZNF750, and GRHL3) for genes that code for differentiation promoting transcription factors were increased (Fig. 1c and Supplementary Fig. 1f). Keratin 1 (K1), a differentiation specific cytoskeletal protein, which is normally only expressed beginning in the suprabasal layer was robustly expressed in the basal layer of HNRNPKi tissue suggesting that the stem cell compartment had prematurely differentiated (Fig. 1d, e).
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