title: Genome-wide characterisation of Foxa1 binding sites reveals several mechanisms for regulating neuronal differentiation in midbrain dopamine cells.
abstract: Midbrain dopamine neuronal progenitors develop into heterogeneous subgroups of neurons, such as substantia nigra pars compacta, ventral tegmental area and retrorubal field, that regulate motor control, motivated and addictive behaviours. The development of midbrain dopamine neurons has been extensively studied, and these studies indicate that complex cross-regulatory interactions between extrinsic and intrinsic molecules regulate a precise temporal and spatial programme of neurogenesis in midbrain dopamine progenitors. To elucidate direct molecular interactions between multiple regulatory factors during neuronal differentiation in mice, we characterised genome-wide binding sites of the forkhead/winged helix transcription factor Foxa1, which functions redundantly with Foxa2 to regulate the differentiation of mDA neurons. Interestingly, our studies identified a rostral brain floor plate Neurog2 enhancer that requires direct input from Otx2, Foxa1, Foxa2 and an E-box transcription factor for its transcriptional activity. Furthermore, the chromatin remodelling factor Smarca1 was shown to function downstream of Foxa1 and Foxa2 to regulate differentiation from immature to mature midbrain dopaminergic neurons. Our genome-wide Foxa1-bound cis-regulatory sequences from ChIP-Seq and Foxa1/2 candidate target genes from RNA-Seq analyses of embryonic midbrain dopamine cells also provide an excellent resource for probing mechanistic insights into gene regulatory networks involved in the differentiation of midbrain dopamine neurons.
authors: Department of Developmental Neurobiology, NIMR, The Ridgeway, London NW7 1AA, UK.
authors: Emmanouil
authors: E
authors: Metzakopian
authors: Department of Developmental Neurobiology, NIMR, The Ridgeway, London NW7 1AA, UK.
authors: Kamal
authors: K
authors: Bouhali
authors: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 Department of Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
authors: Matías
authors: M
authors: Alvarez-Saavedra
authors: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors: Jeffrey A
authors: JA
authors: Whitsett
authors: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 Departments of Biochemistry, Microbiology & Immunology, University of Ottawa, Ontario, Canada K1H 8M5.
authors: David J
authors: DJ
authors: Picketts
authors: Department of Developmental Neurobiology, NIMR, The Ridgeway, London NW7 1AA, UK sang@nimr.mrc.ac.uk.
authors: Siew-Lan
authors: SL
authors: Ang
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D005855:Germ Layers / Q000166:cytology; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D059372:Nucleotide Motifs / Q000235:genetics; D051857:Otx Transcription Factors / Q000378:metabolism; D011485:Protein Binding; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051541:Hepatocyte Nuclear Factor 3-alpha; D051542:Hepatocyte Nuclear Factor 3-beta; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051857:Otx Transcription Factors; D014157:Transcription Factors; C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; C102938:Neurog2 protein, mouse; C497660:Otx2 protein, mouse; C499335:Smarca1 protein, mouse
keywords: ChIP-Seq; Chromatin; Dopaminergic neuronal differentiation; Foxa1; Foxa2; Mouse; RNA-Seq