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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 compromises neural stem cells and neuronal precursors.(A-C) Immunofluorescence microscopy to detect Sox2+ neural stem cells (NSCs) on peri- or postnatal brain sections. At P0, Sox2+ NSCs were enriched in the wild-type dentate gyrus (DG) and this population was smaller in the mutant, as quantified in (D). At P10 and P14, Sox2+ NSCs settled in the control subgranular zone (SGZ), while in the mutant, the granule cell layers were hypoplastic and the SGZ harbored few Sox2+ NSCs. (D) Quantification of Sox2+ cells in the control and mutant dentate gyri at P0. There were significantly fewer Sox2+ NSCs within the mutant dentate gyrus per section (right). The number of Sox2+ cells per mm2 within the dentate gyrus also significantly decreased (left). The quantification was based on three pairs of neonates and at least three matched sections per brain. **p<0.01; ***p<0.001. (E) In the hippocampus, Ctip2 expression was restricted to the CA regions and the suprapyramidal blade of the developing dentate gyrus (DG-s) at P0. (F) Quantification of Ctip2+ cells in the wild-type and mutant suprapyramidal blades, outlined in (E), was based on three pairs of neonates and at least three matched sections per brain. ***p<0.001. (G-I) Dcx expression in control and bKO brain sections at three developmental stages. In the mutant dentate gyrus, there were fewer Dcx+ neuronal precursors apparently at P10 (H) and P24 (I). Scale bars: (A-C), 100 μm; (E), 400 μm, (G-I), 100 μm.
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pgen.1005034.g004: Brpf1 loss compromises neural stem cells and neuronal precursors.(A-C) Immunofluorescence microscopy to detect Sox2+ neural stem cells (NSCs) on peri- or postnatal brain sections. At P0, Sox2+ NSCs were enriched in the wild-type dentate gyrus (DG) and this population was smaller in the mutant, as quantified in (D). At P10 and P14, Sox2+ NSCs settled in the control subgranular zone (SGZ), while in the mutant, the granule cell layers were hypoplastic and the SGZ harbored few Sox2+ NSCs. (D) Quantification of Sox2+ cells in the control and mutant dentate gyri at P0. There were significantly fewer Sox2+ NSCs within the mutant dentate gyrus per section (right). The number of Sox2+ cells per mm2 within the dentate gyrus also significantly decreased (left). The quantification was based on three pairs of neonates and at least three matched sections per brain. **p<0.01; ***p<0.001. (E) In the hippocampus, Ctip2 expression was restricted to the CA regions and the suprapyramidal blade of the developing dentate gyrus (DG-s) at P0. (F) Quantification of Ctip2+ cells in the wild-type and mutant suprapyramidal blades, outlined in (E), was based on three pairs of neonates and at least three matched sections per brain. ***p<0.001. (G-I) Dcx expression in control and bKO brain sections at three developmental stages. In the mutant dentate gyrus, there were fewer Dcx+ neuronal precursors apparently at P10 (H) and P24 (I). Scale bars: (A-C), 100 μm; (E), 400 μm, (G-I), 100 μm.

Mentions: The subgranular zone of the dentate gyrus is one of two major sites harboring adult neural stem cells [68]. As noted above, Sox2 is a neural stem cell marker and its loss leads to dentate gyrus hypoplasia [61]. In addition, Ki67+ neuronal precursors disappeared in the subgranular zone of the mutant dentate gyrus (Fig. 3D-E). These observations suggest that Brpf1 loss may deregulate neural stem cells. To investigate this possibility, we performed immunostaining of brain sections with an antibody against Sox2. At P0, Sox2+ neural stem cells were enriched in the wild-type dentate gyrus (Fig. 4A, left two panels). This population was smaller in the mutant dentate gyrus (Fig. 4A, right two panels & Fig. 4D). In support of this, when compared to the wild-type dentate gyrus, the mutant contained a much smaller population of neurons expressing Ctip2 (Fig. 4E-F), a transcription factor important for dentate gyrus development [71]. As development progressed to P10 and P14, wild-type Sox2+ neural stem cells became enriched in the subgranular zone (Fig. 4B-C, left two panels). By contrast, no such enrichment was present in the mutant (Fig. 4B-C, right two panels), suggesting the requirement of Brpf1 for development of Sox2+ neural stem cells in the 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 compromises neural stem cells and neuronal precursors.(A-C) Immunofluorescence microscopy to detect Sox2+ neural stem cells (NSCs) on peri- or postnatal brain sections. At P0, Sox2+ NSCs were enriched in the wild-type dentate gyrus (DG) and this population was smaller in the mutant, as quantified in (D). At P10 and P14, Sox2+ NSCs settled in the control subgranular zone (SGZ), while in the mutant, the granule cell layers were hypoplastic and the SGZ harbored few Sox2+ NSCs. (D) Quantification of Sox2+ cells in the control and mutant dentate gyri at P0. There were significantly fewer Sox2+ NSCs within the mutant dentate gyrus per section (right). The number of Sox2+ cells per mm2 within the dentate gyrus also significantly decreased (left). The quantification was based on three pairs of neonates and at least three matched sections per brain. **p<0.01; ***p<0.001. (E) In the hippocampus, Ctip2 expression was restricted to the CA regions and the suprapyramidal blade of the developing dentate gyrus (DG-s) at P0. (F) Quantification of Ctip2+ cells in the wild-type and mutant suprapyramidal blades, outlined in (E), was based on three pairs of neonates and at least three matched sections per brain. ***p<0.001. (G-I) Dcx expression in control and bKO brain sections at three developmental stages. In the mutant dentate gyrus, there were fewer Dcx+ neuronal precursors apparently at P10 (H) and P24 (I). Scale bars: (A-C), 100 μm; (E), 400 μm, (G-I), 100 μm.
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pgen.1005034.g004: Brpf1 loss compromises neural stem cells and neuronal precursors.(A-C) Immunofluorescence microscopy to detect Sox2+ neural stem cells (NSCs) on peri- or postnatal brain sections. At P0, Sox2+ NSCs were enriched in the wild-type dentate gyrus (DG) and this population was smaller in the mutant, as quantified in (D). At P10 and P14, Sox2+ NSCs settled in the control subgranular zone (SGZ), while in the mutant, the granule cell layers were hypoplastic and the SGZ harbored few Sox2+ NSCs. (D) Quantification of Sox2+ cells in the control and mutant dentate gyri at P0. There were significantly fewer Sox2+ NSCs within the mutant dentate gyrus per section (right). The number of Sox2+ cells per mm2 within the dentate gyrus also significantly decreased (left). The quantification was based on three pairs of neonates and at least three matched sections per brain. **p<0.01; ***p<0.001. (E) In the hippocampus, Ctip2 expression was restricted to the CA regions and the suprapyramidal blade of the developing dentate gyrus (DG-s) at P0. (F) Quantification of Ctip2+ cells in the wild-type and mutant suprapyramidal blades, outlined in (E), was based on three pairs of neonates and at least three matched sections per brain. ***p<0.001. (G-I) Dcx expression in control and bKO brain sections at three developmental stages. In the mutant dentate gyrus, there were fewer Dcx+ neuronal precursors apparently at P10 (H) and P24 (I). Scale bars: (A-C), 100 μm; (E), 400 μm, (G-I), 100 μm.
Mentions: The subgranular zone of the dentate gyrus is one of two major sites harboring adult neural stem cells [68]. As noted above, Sox2 is a neural stem cell marker and its loss leads to dentate gyrus hypoplasia [61]. In addition, Ki67+ neuronal precursors disappeared in the subgranular zone of the mutant dentate gyrus (Fig. 3D-E). These observations suggest that Brpf1 loss may deregulate neural stem cells. To investigate this possibility, we performed immunostaining of brain sections with an antibody against Sox2. At P0, Sox2+ neural stem cells were enriched in the wild-type dentate gyrus (Fig. 4A, left two panels). This population was smaller in the mutant dentate gyrus (Fig. 4A, right two panels & Fig. 4D). In support of this, when compared to the wild-type dentate gyrus, the mutant contained a much smaller population of neurons expressing Ctip2 (Fig. 4E-F), a transcription factor important for dentate gyrus development [71]. As development progressed to P10 and P14, wild-type Sox2+ neural stem cells became enriched in the subgranular zone (Fig. 4B-C, left two panels). By contrast, no such enrichment was present in the mutant (Fig. 4B-C, right two panels), suggesting the requirement of Brpf1 for development of Sox2+ neural stem cells in the 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