A potential molecular pathogenesis of cardiac/laterality defects in Oculo-Facio-Cardio-Dental syndrome.
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 left lateral 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 left LPM 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 left LPM from the inhibitory activity of Notch signaling. These studies indicated that uncontrolled Notch activity in the left LPM 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 left LPM. The study presented here uncovers the regulatory mechanism of Pitx2 gene transcription which may contribute to an understanding of pathogenesis of OFCD syndrome.
Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA.
Koichi
K
Tanaka
Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA.
Akiko
A
Kato
Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA.
Chelsea
C
Angelocci
Institute of Socio-Arts and Sciences, The University of Tokushima, Tokushima 770-8502, Japan.
Minoru
M
Watanabe
Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA. Electronic address: yoichi.kato@med.fsu.edu.
Yoichi
Y
Kato
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D019521:Body Patterning / Q000235:genetics; D002386:Cataract / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology / Q000254:growth & development; D006330:Heart Defects, Congenital / Q000235:genetics; D006343:Heart Septal Defects / Q000235:genetics* / Q000473:pathology; D059446:Heterotaxy Syndrome / Q000235:genetics*; D056284:Histone Deacetylase 1 / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D008850:Microphthalmos / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D011485:Protein Binding; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D056284:Histone Deacetylase 1; D018398:Homeodomain Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D051785:Smad Proteins; D014157:Transcription Factors; D029867:Xenopus Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C504431:Esr1 protein, Xenopus; C102067:FOXH1 protein, Xenopus; C549535:NOTCH1 protein, Xenopus; C438619:Pitx2b protein, Xenopus; C438620:Pitx2c protein, Xenopus; C512833:nodal1 protein, Xenopus
Left–right patterning; Notch signaling; OFCD syndrome; Pitx2; Xenopus