MOZ and NSC/Ps
MOZ regulates the expression of the tumour suppressor p16Ink4a and entry into replicative senescence of neuronal and haematopoietic stem cells
The histone acetyl-transferase MOZ (Monocytic Leukaemia Zinc Finger protein; MYST3, or KAT6A) is a key regulator of haematopoiesis, frequently found translocated in acute myeloid leukaemia. Previous studies have revealed a crucial role of MOZ in controlling haematopoietic stem cells and progenitors (HSC/Ps) proliferation.
We recently established that this effect is not limited to the haematopoietic compartment, but extends to neuronal stem cells and progenitors (NSC/Ps), suggesting that these two types of cells, HSCs and NSCs, use the same mechanism involving MOZ-driven acetylation in order to maintain their capacity to proliferate. We then demonstrated that the HAT activity of MOZ is critical for silencing of expression of the tumour suppressor p16Ink4a. In the absence of MOZ HAT activity, expression of p16INK4a is up-regulated in haematopoietic and neuronal progenitor and stem cells, inducing an early entrance into replicative senescence and loss of self-renewal. Silencing of p16INK4a by genetic deletion reverses the proliferative defect in both MozHAT-/- haematopoietic and neural progenitors.
Figure 1: The Histone Acetyl Transferase (HAT) activity of MOZ regulates proliferation of haematopoietic and neuronal stem cells MOZ histone acetyl transferase activity prevents entry into early replicative senescence by regulating the expression of the tumour suppressor p16INK4a. In the absence of MOZ HAT activity, the levels of p16INK4a are significantly increased in both haematopoietic and neural stem cell compartments. Upon p16INK4a expression upregulation, these cells leave the cell cycle to become senescent, resulting in severely impaired haematopoietic and neural stem cell self-renewal.
Altogether, these results provide new insights into the control of stem and progenitor cell proliferation and identify an unexpected role of MOZ-mediated acetylation in the regulation of p16INK4a expression (Figure 1). We propose that this mechanism could also be critical for the self-renewal of other types of stem cells. These findings also suggest that, in the context of leukaemia, the repressive activity mediated by MOZ acetylation on the expression of the tumour suppressor p16Ink4a might be further exacerbated in fusion proteins created upon translocations at the human MOZ locus. As such, these MOZ leukaemic fusion proteins would inhibit the triggering of senescence and favour the development of leukaemia.