Regulation of Human Epidermal Stem Cell Proliferation and Senescence Requires Polycomb- Dependent and -Independent Functions of Cbx4

Abstract

Human epidermal stem cells transit from a slow cycling to an actively proliferating state to contribute to homeostasis. Both stem cell states differ in their cell cycle profiles but must remain guarded from differentiation and senescence. Here we show that Cbx4, a Polycomb Repressive Complex 1 (PRC1)-associated protein, maintains human epidermal stem cells as slow-cycling and undifferentiated, while protecting them from senescence. Interestingly, abrogating the polycomb activity of Cbx4 impairs its antisenescent function without affecting stem cell differentiation, indicating that differentiation and senescence are independent processes in human epidermis. Conversely, Cbx4 inhibits stem cell activation and differentiation through its SUMO ligase activity. Global transcriptome and chromatin occupancy analyses indicate that Cbx4 regulates modulators of epidermal homeostasis and represses factors such as Ezh2, Dnmt1, and Bmi1 to prevent the active stem cell state. Our results suggest that distinct Polycomb complexes balance epidermal stem cell dormancy and activation, while continually preventing senescence and differentiation.

microRNA-195 functions as a tumor suppressor by inhibiting CBX4 in hepatocellular carcinoma

“…It encodes a polycomb repressive complex 1 (PRC1)-associated protein (CBX4 protein) that is a member of the Polycomb group (PcG) proteins involved in chromatin remodeling and transcriptional regulation (18). The chromobox family includes five members: CBX2, CBX4, CBX6, CBX7 and CBX8 (19).…”

Oncogenic Ras: A double-edged sword for human epidermal stem and transient amplifying cells

“…8 In addition, Cbx4, a PRC1 associated protein, maintains SCs in an undifferentiated state by regulating Polycomb Group (PcG) proteins (Ezh2, Dnmt1 and Bmi-1) and preventing the active SC state. 12 Of note, genetic and epigenetic mechanisms determine p16 loss and Bmi-1 overexpression in skin tumors. 6,13 The transcription factor p63 is crucial for epithelia development in mice.…”

The Epigenetic Regulation of Wound Healing

“…Within the skin, PcG proteins appear to protect the quiescent state of stem cells, 47 as well as playing roles in regulating epidermal differentiation and stratification. 48 In developing skin, Ezh2 is expressed in basal keratinocytes while Ezh1 is seen in the suprabasal epidermis.…”

“…29,36,42,48,58 In contrast, overexpression of Cbx4 and Chd4 impairs epidermal proliferation. 47,53 But what effect do epigenetic regulators have on proliferation and differentiation during skin repair?…”

“…29,42,48 JMJD3 overexpression leads to accelerated differentiation (Sen et al) while Cbx4 deletion enhances keratinocyte differentiation. 36,47 Their role in re-stratification following injury, however, remains to be elucidated.…”