Global Developmental Gene Programing Involves a Nuclear Form of Fibroblast Growth Factor Receptor-1 (FGFR1).
Genetic studies have placed the Fgfr1 gene at the top of major ontogenic pathways that enable gastrulation, tissue development and organogenesis. Using genome-wide sequencing and loss and gain of function experiments the present investigation reveals a mechanism that underlies global and direct gene regulation by the nuclear form of FGFR1, ensuring that pluripotent Embryonic Stem Cells differentiate into Neuronal Cells in response to Retinoic Acid. Nuclear FGFR1, both alone and with its partner nuclear receptors RXR and Nur77, targets thousands of active genes and controls the expression of pluripotency, homeobox, neuronal and mesodermal genes. Nuclear FGFR1 targets genes in developmental pathways represented by Wnt/β-catenin, CREB, BMP, the cell cycle and cancer-related TP53 pathway, neuroectodermal and mesodermal programing networks, axonal growth and synaptic plasticity pathways. Nuclear FGFR1 targets the consensus sequences of transcription factors known to engage CREB-binding protein, a common coregulator of transcription and established binding partner of nuclear FGFR1. This investigation reveals the role of nuclear FGFR1 as a global genomic programmer of cell, neural and muscle development.
Department of Pathology and Anatomical Sciences, Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, New York, United States of America.
Christopher
C
Terranova
Department of Pathology and Anatomical Sciences, Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, New York, United States of America.
Sridhar T
ST
Narla
Department of Pathology and Anatomical Sciences, Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, New York, United States of America.
Yu-Wei
YW
Lee
Next-Generation Sequencing and Expression Analysis Core, State University of New York at Buffalo, Buffalo, New York, United States of America.
Jonathan
J
Bard
Department of Chemical and Biological Engineering, Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, New York, United States of America.
Abhirath
A
Parikh
Department of Pathology and Anatomical Sciences, Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, New York, United States of America.
Ewa K
EK
Stachowiak
Department of Chemical and Biological Engineering, Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, New York, United States of America.
Emmanuel S
ES
Tzanakakis
Department of Biochemistry, Genomics and Bioinformatics Core, Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, New York, United States of America.
Michael J
MJ
Buck
Department of Pathology and Anatomical Sciences, Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, New York, United States of America.
Barbara
B
Birkaya
Department of Pathology and Anatomical Sciences, Western New York Stem Cell Culture and Analysis Center, State University of New York at Buffalo, Buffalo, New York, United States of America.
Michal K
MK
Stachowiak
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053263:Gene Regulatory Networks; D016678:Genome; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D005810:Multigene Family; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
D002843:Chromatin; D018398:Homeodomain Proteins; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D051496:Receptor, Fibroblast Growth Factor, Type 1