title: Identification of in vivo DNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development.
abstract: The transcription factor Pax6 is comprised of the paired domain (PD) and homeodomain (HD). In the developing forebrain, Pax6 is expressed in ventricular zone precursor cells and in specific subpopulations of neurons; absence of Pax6 results in disrupted cell proliferation and cell fate specification. Pax6 also regulates the entire lens developmental program. To reconstruct Pax6-dependent gene regulatory networks (GRNs), ChIP-seq studies were performed using forebrain and lens chromatin from mice. A total of 3514 (forebrain) and 3723 (lens) Pax6-containing peaks were identified, with ∼70% of them found in both tissues and thereafter called 'common' peaks. Analysis of Pax6-bound peaks identified motifs that closely resemble Pax6-PD, Pax6-PD/HD and Pax6-HD established binding sequences. Mapping of H3K4me1, H3K4me3, H3K27ac, H3K27me3 and RNA polymerase II revealed distinct types of tissue-specific enhancers bound by Pax6. Pax6 directly regulates cortical neurogenesis through activation (e.g. Dmrta1 and Ngn2) and repression (e.g. Ascl1, Fezf2, and Gsx2) of transcription factors. In lens, Pax6 directly regulates cell cycle exit via components of FGF (Fgfr2, Prox1 and Ccnd1) and Wnt (Dkk3, Wnt7a, Lrp6, Bcl9l, and Ccnd1) signaling pathways. Collectively, these studies provide genome-wide analysis of Pax6-dependent GRNs in lens and forebrain and establish novel roles of Pax6 in organogenesis.
authors.affiliation: The Departments of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: The Departments of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Shira
authors.initials: S
authors.lastname: Rockowitz
authors.affiliation: The Departments of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Sackler School of Medicine and Sagol School of Neuroscience, Tel-Aviv University, 69978 Ramat Aviv, Tel Aviv, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ashery-Padan
authors.affiliation: The Departments of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA deyou.zheng@einstein.yu.edu.
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.affiliation: The Departments of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, NY 10461, USA ales.cvekl@einstein.yu.edu.
authors.forename: Ales
authors.initials: A
authors.lastname: Cvekl
mesh_terms: D000818:Animals; D001665:Binding Sites; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007908:Lens, Crystalline / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000235:genetics*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016548:Prosencephalon / Q000196:embryology / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D004247:DNA