The Lysine Acetyltransferase Activator Brpf1 Governs Dentate Gyrus Development through Neural Stem Cells and Progenitors

Abstract

Lysine acetylation has recently emerged as an important post-translational modification in diverse organisms, but relatively little is known about its roles in mammalian development and stem cells. Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multidomain histone binder and a master activator of three lysine acetyltransferases, MOZ, MORF and HBO1, which are also known as KAT6A, KAT6B and KAT7, respectively. While the MOZ and MORF genes are rearranged in leukemia, the MORF gene is also mutated in prostate and other cancers and in four genetic disorders with intellectual disability. Here we show that forebrain-specific inactivation of the mouse Brpf1 gene causes hypoplasia in the dentate gyrus, including underdevelopment of the suprapyramidal blade and complete loss of the infrapyramidal blade. We trace the developmental origin to compromised Sox2 ⁺ neural stem cells and Tbr2 ⁺ intermediate neuronal progenitors. We further demonstrate that Brpf1 loss deregulates neuronal migration, cell cycle progression and transcriptional control, thereby causing abnormal morphogenesis of the hippocampus. These results link histone binding and acetylation control to hippocampus development and identify an important epigenetic regulator for patterning the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis.

Author Summary

Lysine acetylation refers to addition of the acetyl group to lysine residues after protein synthesis. Little is known about how this modification plays a role in the brain and neural stem cells. It is catalyzed by a group of enzymes known as lysine acetyltransferases. A novel epigenetic regulator called BRPF1 acts as a master activator of three different lysine acetyltransferases and also contains multiple structural domains for histone binding. In this study, we show that forebrain-specific inactivation of the mouse Brpf1 gene causes abnormal development of the dentate gyrus, a key component of the hippocampus. We trace the developmental origin to compromised neural stem cells and progenitors, and demonstrate that Brpf1 loss deregulates neuronal migration and cell cycle progression during development of the dentate gyrus. This is the first report on an epigenetic regulator whose loss has such a profound impact on the hippocampus, especially the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis.