Anne Voss-Projects

Anne Voss-Projects

Projects

Chromatin modifier delineates adult neural stem cell lineage

Adult neural stem cells (NSCs) reside in the subventricular zone (SVZ) and produce neurons throughout life. Although their regenerative potential has kindled much interest, few factors regulating NSCs in vivo are known. Among these is the histone acetyltransferase querkopf (QKF, MYST4, KAT6B), which is strongly expressed in a small subset of cells in the neurogenic subventricular zone.

We showed that the 10 per cent of SVZ cells with the highest Qkf gene expression possess the defining NSC characteristics of multipotency and self-renewal and express markers previously shown to enrich for NSCs. A fraction of cells expressing Qkf at medium to high levels is enriched for multipotent progenitor cells with limited self-renewal capacity, followed by a population containing migrating neuroblasts. Cells low in Qkf promoter activity are predominantly ependymal cells. In addition, we show that mice deficient for BMI1, a central regulator of NSC self-renewal, show an age-dependent decrease in the strongest Qkf-expressing cell population in the SVZ.

Our results show a strong relationship between Qkf promoter activity and stem cell characteristics, and a progressive decrease in Qkf gene activity as lineage commitment and differentiation proceed in vivo.

Chromatin-mediated regulation of haematopoietic stem cells

Monocytic leukaemia zinc finger protein (MOZ, MYST3, KAT6A), a transcriptional coactivator and member of the MYST family of histone acetyltransferases, is the target of recurrent translocations in acute myeloid leukaemia. Since genes associated with translocations in leukaemia are commonly important regulators of blood formation, we investigated if MOZ has a role in normal haematopoiesis. We found that MOZ-deficient foetal liver haematopoietic cells were incapable of contributing to the haematopoietic system of recipients after transplantation. We observed profound defects in a MOZ-deficient stem cell compartment. Progenitors of all lineages were reduced in number. However, blood cell lineage commitment was unaffected. Together, these results show that MOZ is essential for a fundamental property of haematopoietic stem cells, the ability to reconstitute the haematopoietic system of a recipient after transplantation and that MOZ is specifically required in the stem cell compartment.

Chromatin modifier required by adult neural stem cells

The adult mammalian brain maintains populations of neural stem cells within discrete proliferative zones. Understanding of the molecular mechanisms regulating adult neural stem cell function is limited.

We showed that a deficiency in MYST family histone acetyltransferase querkopf (QKF, MYST4, KAT6B) leads to cumulative defects in adult neurogenesis in vivo, resulting in declining numbers of olfactory bulb interneurons, a population of neurons produced in large numbers during adulthood. QKF-deficiency reduces the number of neural stem cells and migrating neuroblasts in the rostral migratory stream. Qkf gene expression is strong in the neurogenic subventricular zone. A population enriched in multipotent cells can be isolated from this region on the basis of Qkf gene expression. Neural stem and progenitor cells isolated from Qkf mutants exhibited a reduced self-renewal capacity and a reduced ability to produce differentiated neurons. Together, our data show that QKF is essential for normal adult neurogenesis.