title: Program specificity for Ptf1a in pancreas versus neural tube development correlates with distinct collaborating cofactors and chromatin accessibility.
abstract: The lineage-specific basic helix-loop-helix transcription factor Ptf1a is a critical driver for development of both the pancreas and nervous system. How one transcription factor controls diverse programs of gene expression is a fundamental question in developmental biology. To uncover molecular strategies for the program-specific functions of Ptf1a, we identified bound genomic regions in vivo during development of both tissues. Most regions bound by Ptf1a are specific to each tissue, lie near genes needed for proper formation of each tissue, and coincide with regions of open chromatin. The specificity of Ptf1a binding is encoded in the DNA surrounding the Ptf1a-bound sites, because these regions are sufficient to direct tissue-restricted reporter expression in transgenic mice. Fox and Sox factors were identified as potential lineage-specific modifiers of Ptf1a binding, since binding motifs for these factors are enriched in Ptf1a-bound regions in pancreas and neural tube, respectively. Of the Fox factors expressed during pancreatic development, Foxa2 plays a major role. Indeed, Ptf1a and Foxa2 colocalize in embryonic pancreatic chromatin and can act synergistically in cell transfection assays. Together, these findings indicate that lineage-specific chromatin landscapes likely constrain the DNA binding of Ptf1a, and they identify Fox and Sox gene families as part of this process.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Meredith
authors.forename: Mark D
authors.initials: MD
authors.lastname: Borromeo
authors.forename: Tye G
authors.initials: TG
authors.lastname: Deering
authors.forename: Bradford H
authors.initials: BH
authors.lastname: Casey
authors.forename: Trisha K
authors.initials: TK
authors.lastname: Savage
authors.forename: Paul R
authors.initials: PR
authors.lastname: Mayer
authors.forename: Chinh
authors.initials: C
authors.lastname: Hoang
authors.forename: Kuang-Chi
authors.initials: KC
authors.lastname: Tung
authors.forename: Manonmani
authors.initials: M
authors.lastname: Kumar
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Shen
authors.forename: Galvin H
authors.initials: GH
authors.lastname: Swift
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Macdonald
authors.forename: Jane E
authors.initials: JE
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D016384:Consensus Sequence; D004247:DNA / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D054259:Neural Tube / Q000196:embryology* / Q000378:metabolism; D010179:Pancreas / Q000196:embryology* / Q000378:metabolism; D011485:Protein Binding; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002843:Chromatin; C496503:Foxa2 protein, mouse; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; C062602:transcription factor PTF1; D051542:Hepatocyte Nuclear Factor 3-beta; D004247:DNA