Deficiency of the Chromatin Regulator Brpf1 Causes Abnormal Brain Development*

Linya You, Jinfeng Zou, Hong Zhao, Nicholas R Bertos, Morag Park, Edwin Wang, Xiang-Jiao Yang

Epigenetic mechanisms are important in different neurological disorders and one such mechanism is histone acetylation. The multivalent chromatin regulator BRPF1 (bromodomain- and PHD finger-containing protein 1) recognizes different epigenetic marks and activates three histone acetyltransferases, so it is both a reader and a co-writer of the epigenetic language. The three histone acetyltransferases are MOZ, MORF and HBO1, which are also known as lysine acetyltransferase 6A (KAT6A), KAT6B and KAT7, respectively. The MORF gene is mutated in four neurodevelopmental disorders sharing the characteristic of intellectual disability and frequently displaying callosal agenesis. Here we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities and partial callosal agenesis. With respect to the control, the mutant forebrain contained fewer Tbr2-positive intermediate neuronal progenitors and displayed aberrant neurogenesis. Molecularly, Brpf1 loss led to decreased transcription of multiple genes, such as Robo3 and Otx1, important for neocortical development. Surprisingly, elevated expression of different Hox genes and various other transcription factors, such as Lhx4, Foxa1, Tbx5 and Twist1, was also observed. These results thus identify an important role of Brpf1 in regulating forebrain development and suggest that it acts as both an activator and a silencer of gene expression in vivo.