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Dev Biol
2014 Mar 01;3871:28-36. doi: 10.1016/j.ydbio.2014.01.003.
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A potential molecular pathogenesis of cardiac/laterality defects in Oculo-Facio-Cardio-Dental syndrome.
Tanaka K
,
Kato A
,
Angelocci C
,
Watanabe M
,
Kato Y
.
???displayArticle.abstract??? Pitx2 is the last effector of the left-right (LR) cascade known to date and plays a crucial role in the patterning of LR asymmetry. In Xenopus embryos, the expression of Pitx2 gene in the leftlateral plate mesoderm (LPM) is directly regulated by Xnr1 signaling, which is mediated by Smads and FoxH1. Previous studies suggest that the suppression of Pitx2 gene in the leftLPM is a potential cause of cardiac/laterality defects in Oculo-Facio-Cardio-Dental (OFCD) syndrome, which is known to be caused by mutations in BCL6 co-repressor (BCOR) gene. Recently, our work has revealed that the BCL6/BCOR complex blocks Notch-dependent transcriptional activity to protect the expression of Pitx2 in the leftLPM from the inhibitory activity of Notch signaling. These studies indicated that uncontrolled Notch activity in the leftLPM caused by dysfunction of BCOR may result in cardiac/laterality defects of OFCD syndrome. However, this Notch-dependent inhibitory mechanism of Pitx2 gene transcription still remains unknown. Here we report that transcriptional repressor ESR1, which acts downstream of Notch signaling, inhibits the expression of Pitx2 gene by binding to a left side-specific enhancer (ASE) region in Pitx2 gene and recruiting histone deacetylase 1 (HDAC1) to this region. Once HDAC1 is tethered, histone acetyltransferase p300 is no longer recruited to the Xnr1-dependent transcriptional complex on the ASE region, leading to the suppression of Pitx2 gene in the leftLPM. The study presented here uncovers the regulatory mechanism of Pitx2 gene transcription which may contribute to an understanding of pathogenesis of OFCD syndrome.
Fig. 1. The Xnr1-dependent transcriptional complex is a potential target of Notch signaling. (A) The experimental strategy. (B) One pg Xnr1 or 50 pg GR-FoxH1-VP16 RNA were injected into a rightventralblastomere of 4-cell-stage embryos with or without 2 ng GR-NICD or 1 ng GR-ESR1 RNA. DEX was added into the culture medium at stage 22. The expression of Pitx2 at stage 25 was tested by whole mount in situ hybridization. (C) The quantitative assessment of the injections in (B). At least three independent experiments were performed. “n†indicates the number of injected embryos. R: Injection into the right side of embryo.
Fig. 2. ESR1 directly blocked the expression of Pitx2 gene in the leftLPM. (A) The experimental strategy. (B) One ng GR-NICD or 1 ng GR-ESR1 RNA was injected into a leftventralblastomere of 4-cell-stage embryos. DEX was added into the culture medium at stage 22 and CHX was added 30 min before the addition of DEX. (C) The quantitative assessment of the injections in (B). At least three independent experiments were performed. “n†indicates the number of injected embryos. L: Injection into the left side of embryo.
Fig. 3. ESR1 and FoxH1 independently bind to the ASE region in Pitx2 gene. (A) Nucleotide sequence of the ASE region in Xenopus Pitx2 gene. Three FoxH1-binding sites (red boxes), one N-box (blue box) and five E-boxes (green letters) are indicated within the ASE region. (B) The experimental strategy of ChIP assay. (C) One ng HA-ESR1 RNA was injected into 2-cell-stage embryos, and embryonic extracts were isolated at stage 10 for ChIP analysis. ChIP assays were performed using α-HA antibody. (D) One ng myc-FoxH1 RNA was injected into 2-cell-stage embryos with or without 1 ng flag-ESR1 RNA, and nuclear extracts were isolated at stage 10 for ChIP analysis. ChIP assays were performed using α-myc antibody.
Fig. 4. ESR1 recruits HDAC1 to the ASE region to exclude p300 from the Xnr1-dependent transcriptional complex. (A) The experimental strategy of animal cap assay. Zygotic transcription starts at stage 8. (B) Twenty pg activin RNA was injected into 2-cell-stage embryos with or without 100 pg E1A RNA and animal caps were dissected at the stage 8. Caps were cultured until sibling embryos reached stage 10, and Pitx2 gene expression was evaluated by semi-quantitative RT-PCR analysis. (C) Two ng flag-p300 RNA and/or 20 pg activin RNA was injected into 2-cell-stage embryos with or without 2 ng HA-ESR1 RNA, and embryonic extracts were isolated at stage 10 for ChIP analysis. ChIP assays were performed using α-flag antibody. (D) Twenty pg activin RNA was injected into 2-cell-stage embryos with or without 2 ng HA-ESR1 RNA, and animal caps were dissected at the stage 8. Caps were cultured with or without 50 nM TSA until sibling embryos reached stage 10, and Pitx2 gene expression was evaluated by semi-quantitative RT-PCR analysis. (E) Twenty pg activin RNA was injected into 2-cell-stage embryos with or without 2 ng HA-ESR1 RNA, and embryonic extracts were isolated at stage 10 for ChIP analysis. ChIP assays were performed using α-HDAC1 antibody.
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