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The lysine acetyltransferase activator Brpf1 governs dentate gyrus development through neural stem cells and progenitors.

You L, Yan K, Zou J, Zhou J, Zhao H, Bertos NR, Park M, Wang E, Yang XJ - PLoS Genet. (2015)

Bottom Line: 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.We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors.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.

View Article: PubMed Central - PubMed

Affiliation: The Rosalind & Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.

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.

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Brpf1 loss deregulates gene expression important for hippocampus development.(A-C) RT-PCR analysis of transcripts for Brpf1 (A), the acetyltransfrases Hbo1 and hMof (B), and five transcription factors (C), loss of which is known to cause dentate gyrus hypoplasia (see the text). The primers used are listed in S1 Table. Gapdh was used as the internal control [57]. At P24, Tbr2 expression is known to be limited to the subgranular zone of the dentate gyrus, so the RT-PCR product was not detected. (D) RT-qPCR analysis of transcripts for Brpf1, four cell cycle inhibitors and six genes important for hippocampus development. The p16/19, p15 and six other genes were identified in the microarray analysis of dorsal brain cortices isolated from three pairs of wild-type and mutant pups at P4 [57]. The RT-qPCR analysis was performed on three pairs of dorsal brain cortices at P12 and the average values are shown with standard deviation. Dct, dopachrome tautomerase; Cplx3, presynaptic protein complexin 3. *, p<0.05; **, p<0.01; ***, p<0.001; ns, not statistically significant.
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pgen.1005034.g009: Brpf1 loss deregulates gene expression important for hippocampus development.(A-C) RT-PCR analysis of transcripts for Brpf1 (A), the acetyltransfrases Hbo1 and hMof (B), and five transcription factors (C), loss of which is known to cause dentate gyrus hypoplasia (see the text). The primers used are listed in S1 Table. Gapdh was used as the internal control [57]. At P24, Tbr2 expression is known to be limited to the subgranular zone of the dentate gyrus, so the RT-PCR product was not detected. (D) RT-qPCR analysis of transcripts for Brpf1, four cell cycle inhibitors and six genes important for hippocampus development. The p16/19, p15 and six other genes were identified in the microarray analysis of dorsal brain cortices isolated from three pairs of wild-type and mutant pups at P4 [57]. The RT-qPCR analysis was performed on three pairs of dorsal brain cortices at P12 and the average values are shown with standard deviation. Dct, dopachrome tautomerase; Cplx3, presynaptic protein complexin 3. *, p<0.05; **, p<0.01; ***, p<0.001; ns, not statistically significant.

Mentions: Having identified the cellular mechanisms for the observed defects in the dentate gyrus, we then investigated the underlying molecular mechanisms. Brpf1 activates Moz, Morf and Hbo1 [30–32]. These acetyltransferases function as transcriptional coregulators [19,76–79]. Thus, we considered whether Brpf1 inactivation deregulates transcription. For this, we first performed RT-PCR. Brpf1 deletion occurred efficiently (Fig. 9A) [57]. The inactivation did not affect mRNA levels of Brpf2, Brpf3, Moz and Morf (S1D Fig). Similarly, neither Hbo1 nor hMof was altered (Fig. 9B). Importantly, mRNA levels of NeuroD1, Tbr2 and FoxG1 were reduced in the mutant (Fig. 9C). This is consistent with the immunofluorescence microscopic results Figs. (6 & S4). The transcript levels of Emx2 and Tlx were also reduced (Fig. 9C). As these transcription factors are known to be important for dentate gyrus development, these results nicely explain hypoplasia of the bKO dentate gyrus.


The lysine acetyltransferase activator Brpf1 governs dentate gyrus development through neural stem cells and progenitors.

You L, Yan K, Zou J, Zhou J, Zhao H, Bertos NR, Park M, Wang E, Yang XJ - PLoS Genet. (2015)

Brpf1 loss deregulates gene expression important for hippocampus development.(A-C) RT-PCR analysis of transcripts for Brpf1 (A), the acetyltransfrases Hbo1 and hMof (B), and five transcription factors (C), loss of which is known to cause dentate gyrus hypoplasia (see the text). The primers used are listed in S1 Table. Gapdh was used as the internal control [57]. At P24, Tbr2 expression is known to be limited to the subgranular zone of the dentate gyrus, so the RT-PCR product was not detected. (D) RT-qPCR analysis of transcripts for Brpf1, four cell cycle inhibitors and six genes important for hippocampus development. The p16/19, p15 and six other genes were identified in the microarray analysis of dorsal brain cortices isolated from three pairs of wild-type and mutant pups at P4 [57]. The RT-qPCR analysis was performed on three pairs of dorsal brain cortices at P12 and the average values are shown with standard deviation. Dct, dopachrome tautomerase; Cplx3, presynaptic protein complexin 3. *, p<0.05; **, p<0.01; ***, p<0.001; ns, not statistically significant.
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pgen.1005034.g009: Brpf1 loss deregulates gene expression important for hippocampus development.(A-C) RT-PCR analysis of transcripts for Brpf1 (A), the acetyltransfrases Hbo1 and hMof (B), and five transcription factors (C), loss of which is known to cause dentate gyrus hypoplasia (see the text). The primers used are listed in S1 Table. Gapdh was used as the internal control [57]. At P24, Tbr2 expression is known to be limited to the subgranular zone of the dentate gyrus, so the RT-PCR product was not detected. (D) RT-qPCR analysis of transcripts for Brpf1, four cell cycle inhibitors and six genes important for hippocampus development. The p16/19, p15 and six other genes were identified in the microarray analysis of dorsal brain cortices isolated from three pairs of wild-type and mutant pups at P4 [57]. The RT-qPCR analysis was performed on three pairs of dorsal brain cortices at P12 and the average values are shown with standard deviation. Dct, dopachrome tautomerase; Cplx3, presynaptic protein complexin 3. *, p<0.05; **, p<0.01; ***, p<0.001; ns, not statistically significant.
Mentions: Having identified the cellular mechanisms for the observed defects in the dentate gyrus, we then investigated the underlying molecular mechanisms. Brpf1 activates Moz, Morf and Hbo1 [30–32]. These acetyltransferases function as transcriptional coregulators [19,76–79]. Thus, we considered whether Brpf1 inactivation deregulates transcription. For this, we first performed RT-PCR. Brpf1 deletion occurred efficiently (Fig. 9A) [57]. The inactivation did not affect mRNA levels of Brpf2, Brpf3, Moz and Morf (S1D Fig). Similarly, neither Hbo1 nor hMof was altered (Fig. 9B). Importantly, mRNA levels of NeuroD1, Tbr2 and FoxG1 were reduced in the mutant (Fig. 9C). This is consistent with the immunofluorescence microscopic results Figs. (6 & S4). The transcript levels of Emx2 and Tlx were also reduced (Fig. 9C). As these transcription factors are known to be important for dentate gyrus development, these results nicely explain hypoplasia of the bKO dentate gyrus.

Bottom Line: 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.We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors.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.

View Article: PubMed Central - PubMed

Affiliation: The Rosalind & Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.

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.

Show MeSH
Related in: MedlinePlus