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Xie, Q.* ; Yang, Y.* ; Huang, J.* ; Ninkovic, J. ; Walcher, T. ; Wolf, L.* ; Vitenzon, A.* ; Zheng, D.Y.* ; Götz, M. ; Beebe, D.C.* ; Zavadil, J.* ; Cvekl, A.*

Pax6 Interactions with chromatin and identification of its novel direct target genes in lens and forebrain.

PLoS ONE 8:e54507 (2013)

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Pax6 encodes a specific DNA-binding transcription factor that regulates the development of multiple organs, including the eye, brain and pancreas. Previous studies have shown that Pax6 regulates the entire process of ocular lens development. In the developing forebrain, Pax6 is expressed in ventricular zone precursor cells and in specific populations of neurons; absence of Pax6 results in disrupted cell proliferation and cell fate specification in telencephalon. In the pancreas, Pax6 is essential for the differentiation of alpha-, beta- and delta-islet cells. To elucidate molecular roles of Pax6, chromatin immunoprecipitation experiments combined with high-density oligonucleotide array hybridizations (ChIP-chip) were performed using three distinct sources of chromatin (lens, forebrain and beta-cells). ChIP-chip studies, performed as biological triplicates, identified a total of 5,260 promoters occupied by Pax6. 1,001 (133) of these promoter regions were shared between at least two (three) distinct chromatin sources, respectively. In lens chromatin, 2,335 promoters were bound by Pax6. RNA expression profiling from Pax6(+/-) lenses combined with in vivo Pax6-binding data yielded 76 putative Pax6-direct targets, including the Gaa, Isl1, Kif1b, Mtmr2, Pcsk1n, and Snca genes. RNA and ChIP data were validated for all these genes. In lens cells, reporter assays established Kib1b and Snca as Pax6 activated and repressed genes, respectively. In situ hybridization revealed reduced expression of these genes in E14 cerebral cortex. Moreover, we examined differentially expressed transcripts between E9.5 wild type and Pax6(-/-) lens placodes that suggested Efnb2, Fat4, Has2, Nav1, and Trpm3 as novel Pax6-direct targets. Collectively, the present studies, through the identification of Pax6-direct target genes, provide novel insights into the molecular mechanisms of Pax6 gene control during mouse embryonic development. In addition, the present data demonstrate that Pax6 interacts preferentially with promoter regions in a tissue-specific fashion. Nevertheless, nearly 20% of the regions identified are accessible to Pax6 in multiple tissues.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Transcription Factor Pax6 ; Alpha-a-crystallin ; Embryonic Stem-cells ; Regulatory Networks ; Eye Development ; Olfactory-bulb ; Paired Domain ; Dna-binding ; Segment Abnormalities ; Neuronal Migration

ISSN (print) / ISBN 1932-6203

Journal PLoS ONE

Quellenangaben Volume: 8, Issue: 1, Article Number: e54507

Publisher Public Library of Science (PLoS)

Publishing Place Lawrence, Kan.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Stem Cell Research (ISF)