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Histone posttranslational modifications and cell fate determination: lens induction requires the lysine acetyltransferases CBP and p300.

ABSTRACT: Lens induction is a classical embryologic model to study cell fate determination. It has been proposed earlier that specific changes in core histone modifications accompany the process of cell fate specification and determination. The lysine acetyltransferases CBP and p300 function as principal enzymes that modify core histones to facilitate specific gene expression. Herein, we performed conditional inactivation of both CBP and p300 in the ectodermal cells that give rise to the lens placode. Inactivation of both CBP and p300 resulted in the dramatic discontinuation of all aspects of lens specification and organogenesis, resulting in aphakia. The CBP/p300(-/-) ectodermal cells are viable and not prone to apoptosis. These cells showed reduced expression of Six3 and Sox2, while expression of Pax6 was not upregulated, indicating discontinuation of lens induction. Consequently, expression of ?B- and ?A-crystallins was not initiated. Mutant ectoderm exhibited markedly reduced levels of histone H3 K18 and K27 acetylation, subtly increased H3 K27me3 and unaltered overall levels of H3 K9ac and H3 K4me3. Our data demonstrate that CBP and p300 are required to establish lens cell-type identity during lens induction, and suggest that posttranslational histone modifications are integral to normal cell fate determination in the mammalian lens.

SUBMITTER: Wolf L

PROVIDER: S-EPMC3905850 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Histone posttranslational modifications and cell fate determination: lens induction requires the lysine acetyltransferases CBP and p300.

Wolf Louise L Harrison Wilbur W Huang Jie J Xie Qing Q Xiao Ningna N Sun Jian J Kong Lingkun L Lachke Salil A SA Kuracha Murali R MR Govindarajan Venkatesh V Brindle Paul K PK Ashery-Padan Ruth R Beebe David C DC Overbeek Paul A PA Cvekl Ales A

Nucleic acids research 20130912 22

Lens induction is a classical embryologic model to study cell fate determination. It has been proposed earlier that specific changes in core histone modifications accompany the process of cell fate specification and determination. The lysine acetyltransferases CBP and p300 function as principal enzymes that modify core histones to facilitate specific gene expression. Herein, we performed conditional inactivation of both CBP and p300 in the ectodermal cells that give rise to the lens placode. Ina ...[more]

PMID: 24038357

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Project description:The enhancer factors CBP/p300 maintain gene expression programs through lysine acetylation of chromatin and transcriptional regulators and by scaffolding functions mediated by several protein-protein interaction domains. We have designed dCBP-1, a compound that induces degradation of CBP/p300, and profiled its activity inducing global proteome changes in HAP1 and MM1S cells. The proteome changes were mapped using multiplexed quantitative proteomics (TMT11) and applying the SPS-MS3 method on either an Orbitrap Fusion or an Orbitrap Lumos Fusion mass spectrometer. The proteome was mapped 3 hours and 6 hours upon drug treatment. Samples were covered over two TMT sets for both time points. Samples for the 3 hours time points (HAP1 and MM1S) were analyzed using a total of 48 fractions on an Orbitrap Lumos mass spectrometer. Samples for the 6 hours time point (MM1S) were analyzed using a total of 20 fractions on an Orbitrap Fusion mass spectrometer. Samples were analyzed in three replicates (rep1-rep3). Pooled tryptic digests were used as bridge channels to compare proteome profiles from the two TMT sets mapped per time point. Samples were labeled as described in the following: 3 hours: HAP1_DMSO_3h_rep1 (Ott_3hours_TMT1_129c); HAP1_DMSO_3h_rep2 (Ott_3hours_TMT1_130n); HAP1_DMSO_3h_rep3 (Ott_3hours_TMT1_130c); HAP1_dCBP1_3h_rep1 (Ott_3hours_TMT2_129c); HAP1_dCBP1_3h_rep2 (Ott_3hours_TMT2_130n); HAP1_dCBP1_3h_rep3 (Ott_3hours_TMT2_130c); MM1S_DMSO_3h_rep1 (Ott_3hours_TMT1_126); MM1S_DMSO_3h_rep2 (Ott_3hours_TMT1_127n); MM1S_DMSO_3h_rep3 (Ott_3hours_TMT1_127c); MM1S_dCBP1_3h_rep1 (Ott_3hours_TMT1_128n); MM1S_dCBP1_3h_rep2 (Ott_3hours_TMT1_128c); MM1S_dCBP1_3h_rep3 (Ott_3hours_TMT1_129n); Bridge channels (Ott_3hours_TMT1 and TMT2, 131n). 6 hours: TMT1_128c (Ott_6hours_TMT1_128c); TMT2_126 (Ott_6hours_TMT2_126); TMT2_129c (Ott_6hours_TMT2_129c); TMT1_129n (Ott_6hours_TMT1_129n); TMT2_127n (Ott_6hours_TMT2_127n); TMT2_130n (Ott_6hours_TMT2_130n); Bridge channels (Ott_6hours_TMT1 and TMT2, 131c).

Dataset Information

Histone posttranslational modifications and cell fate determination: lens induction requires the lysine acetyltransferases CBP and p300.

Publications

Histone posttranslational modifications and cell fate determination: lens induction requires the lysine acetyltransferases CBP and p300.

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