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Essential role of chromatin remodeling protein Bptf in early mouse embryos and embryonic stem cells.

Landry J, Sharov AA, Piao Y, Sharova LV, Xiao H, Southon E, Matta J, Tessarollo L, Zhang YE, Ko MS, Kuehn MR, Yamaguchi TP, Wu C - PLoS Genet. (2008)

Bottom Line: Differentiation of Bptf(-/-) embryonic stem cell lines into embryoid bodies revealed its requirement for development of mesoderm, endoderm, and ectoderm tissue lineages, and uncovered many genes whose activation or repression are Bptf-dependent.We also provide functional and physical links between the Bptf-containing NURF complex and the Smad transcription factors.We conclude that Bptf likely regulates genes and signaling pathways essential for the development of key tissues of the early mouse embryo.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biochemistry and Molecular Cell Biology, National Cancer Institute, National Institutes of Heath, Bethesda, MD, USA. landrjos@mail.nih.gov

ABSTRACT
We have characterized the biological functions of the chromatin remodeling protein Bptf (Bromodomain PHD-finger Transcription Factor), the largest subunit of NURF (Nucleosome Remodeling Factor) in a mammal. Bptf mutants manifest growth defects at the post-implantation stage and are reabsorbed by E8.5. Histological analyses of lineage markers show that Bptf(-/-) embryos implant but fail to establish a functional distal visceral endoderm. Microarray analysis at early stages of differentiation has identified Bptf-dependent gene targets including homeobox transcriptions factors and genes essential for the development of ectoderm, mesoderm, and both definitive and visceral endoderm. Differentiation of Bptf(-/-) embryonic stem cell lines into embryoid bodies revealed its requirement for development of mesoderm, endoderm, and ectoderm tissue lineages, and uncovered many genes whose activation or repression are Bptf-dependent. We also provide functional and physical links between the Bptf-containing NURF complex and the Smad transcription factors. These results suggest that Bptf may co-regulate some gene targets of this pathway, which is essential for establishment of the visceral endoderm. We conclude that Bptf likely regulates genes and signaling pathways essential for the development of key tissues of the early mouse embryo.

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Analysis of Bptf knockout mouse embryonic stem cells shows severe defects in gene expression during differentiation with RA and LIF withdrawal.Bptf knockout embryonic stem (ES) cells were induced to differentiate using LIF withdrawal (LIF−) or the addition of retinoic acid (RA), and gene expression was monitored by microarray. (A) Bptf-dependent genes were defined as genes whose transcription increases or decreases more than 2-fold in the mutant compared to the wild type with a FDR value of <0.05. (B) A manual clustering analysis of Bptf-dependent genes by condition of dependence and expression values. Six expression categories were identified and include genes which are exclusively Bptf-dependent in LIF−, LIF+, or RA conditions, genes which are dependent in all conditions (constitutive regulation), genes which are dependent in 2 conditions (complex regulation), or genes which vary in direction of misregulation between conditions (mixed regulation). (C) Clustering analysis of Bptf-dependent genes important for the development of tissue lineages of the early embryo. Bptf is essential for the proper regulation of many markers of ectoderm, endoderm, and mesoderm tissue lineages.
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pgen-1000241-g004: Analysis of Bptf knockout mouse embryonic stem cells shows severe defects in gene expression during differentiation with RA and LIF withdrawal.Bptf knockout embryonic stem (ES) cells were induced to differentiate using LIF withdrawal (LIF−) or the addition of retinoic acid (RA), and gene expression was monitored by microarray. (A) Bptf-dependent genes were defined as genes whose transcription increases or decreases more than 2-fold in the mutant compared to the wild type with a FDR value of <0.05. (B) A manual clustering analysis of Bptf-dependent genes by condition of dependence and expression values. Six expression categories were identified and include genes which are exclusively Bptf-dependent in LIF−, LIF+, or RA conditions, genes which are dependent in all conditions (constitutive regulation), genes which are dependent in 2 conditions (complex regulation), or genes which vary in direction of misregulation between conditions (mixed regulation). (C) Clustering analysis of Bptf-dependent genes important for the development of tissue lineages of the early embryo. Bptf is essential for the proper regulation of many markers of ectoderm, endoderm, and mesoderm tissue lineages.

Mentions: We chose a microarray approach to investigate any differentiation defects of Bptf knockout ES cells in undifferentiated and early differentiation states. Differentiation was induced by LIF withdrawal (LIF−) or retinoic acid (RA) for three days before harvesting RNA. A comparison of Bptf-dependent genes by Venn diagram and manual clustering identifies six categories; those being affected under only one of the growth conditions (LIF+, LIF− or RA Regulation), those being affected in all three conditions (Constitutive Regulation), a class of genes which were regulated in the same direction in two of three conditions (Complex Regulation) and genes with mixed dependence (Mixed Regulation) (Figure 4A and 4B) (Dataset S1).


Essential role of chromatin remodeling protein Bptf in early mouse embryos and embryonic stem cells.

Landry J, Sharov AA, Piao Y, Sharova LV, Xiao H, Southon E, Matta J, Tessarollo L, Zhang YE, Ko MS, Kuehn MR, Yamaguchi TP, Wu C - PLoS Genet. (2008)

Analysis of Bptf knockout mouse embryonic stem cells shows severe defects in gene expression during differentiation with RA and LIF withdrawal.Bptf knockout embryonic stem (ES) cells were induced to differentiate using LIF withdrawal (LIF−) or the addition of retinoic acid (RA), and gene expression was monitored by microarray. (A) Bptf-dependent genes were defined as genes whose transcription increases or decreases more than 2-fold in the mutant compared to the wild type with a FDR value of <0.05. (B) A manual clustering analysis of Bptf-dependent genes by condition of dependence and expression values. Six expression categories were identified and include genes which are exclusively Bptf-dependent in LIF−, LIF+, or RA conditions, genes which are dependent in all conditions (constitutive regulation), genes which are dependent in 2 conditions (complex regulation), or genes which vary in direction of misregulation between conditions (mixed regulation). (C) Clustering analysis of Bptf-dependent genes important for the development of tissue lineages of the early embryo. Bptf is essential for the proper regulation of many markers of ectoderm, endoderm, and mesoderm tissue lineages.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2570622&req=5

pgen-1000241-g004: Analysis of Bptf knockout mouse embryonic stem cells shows severe defects in gene expression during differentiation with RA and LIF withdrawal.Bptf knockout embryonic stem (ES) cells were induced to differentiate using LIF withdrawal (LIF−) or the addition of retinoic acid (RA), and gene expression was monitored by microarray. (A) Bptf-dependent genes were defined as genes whose transcription increases or decreases more than 2-fold in the mutant compared to the wild type with a FDR value of <0.05. (B) A manual clustering analysis of Bptf-dependent genes by condition of dependence and expression values. Six expression categories were identified and include genes which are exclusively Bptf-dependent in LIF−, LIF+, or RA conditions, genes which are dependent in all conditions (constitutive regulation), genes which are dependent in 2 conditions (complex regulation), or genes which vary in direction of misregulation between conditions (mixed regulation). (C) Clustering analysis of Bptf-dependent genes important for the development of tissue lineages of the early embryo. Bptf is essential for the proper regulation of many markers of ectoderm, endoderm, and mesoderm tissue lineages.
Mentions: We chose a microarray approach to investigate any differentiation defects of Bptf knockout ES cells in undifferentiated and early differentiation states. Differentiation was induced by LIF withdrawal (LIF−) or retinoic acid (RA) for three days before harvesting RNA. A comparison of Bptf-dependent genes by Venn diagram and manual clustering identifies six categories; those being affected under only one of the growth conditions (LIF+, LIF− or RA Regulation), those being affected in all three conditions (Constitutive Regulation), a class of genes which were regulated in the same direction in two of three conditions (Complex Regulation) and genes with mixed dependence (Mixed Regulation) (Figure 4A and 4B) (Dataset S1).

Bottom Line: Differentiation of Bptf(-/-) embryonic stem cell lines into embryoid bodies revealed its requirement for development of mesoderm, endoderm, and ectoderm tissue lineages, and uncovered many genes whose activation or repression are Bptf-dependent.We also provide functional and physical links between the Bptf-containing NURF complex and the Smad transcription factors.We conclude that Bptf likely regulates genes and signaling pathways essential for the development of key tissues of the early mouse embryo.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biochemistry and Molecular Cell Biology, National Cancer Institute, National Institutes of Heath, Bethesda, MD, USA. landrjos@mail.nih.gov

ABSTRACT
We have characterized the biological functions of the chromatin remodeling protein Bptf (Bromodomain PHD-finger Transcription Factor), the largest subunit of NURF (Nucleosome Remodeling Factor) in a mammal. Bptf mutants manifest growth defects at the post-implantation stage and are reabsorbed by E8.5. Histological analyses of lineage markers show that Bptf(-/-) embryos implant but fail to establish a functional distal visceral endoderm. Microarray analysis at early stages of differentiation has identified Bptf-dependent gene targets including homeobox transcriptions factors and genes essential for the development of ectoderm, mesoderm, and both definitive and visceral endoderm. Differentiation of Bptf(-/-) embryonic stem cell lines into embryoid bodies revealed its requirement for development of mesoderm, endoderm, and ectoderm tissue lineages, and uncovered many genes whose activation or repression are Bptf-dependent. We also provide functional and physical links between the Bptf-containing NURF complex and the Smad transcription factors. These results suggest that Bptf may co-regulate some gene targets of this pathway, which is essential for establishment of the visceral endoderm. We conclude that Bptf likely regulates genes and signaling pathways essential for the development of key tissues of the early mouse embryo.

Show MeSH
Related in: MedlinePlus