Issue 6, 2016

Design and development of histone deacetylase (HDAC) chemical probes for cell-based profiling

Abstract

Histone deacetylases (HDACs) contribute to regulation of gene expression by mediating higher-order chromatin structures. They assemble into large multiprotein complexes that regulate activity and specificity. We report the development of small molecule probes with class IIa and pan-HDAC activity that contain photoreactive crosslinking groups and either a biotin reporter, or a terminal alkyne handle for subsequent bioorthogonal ligation. The probes retained inhibitory activity against recombinant HDAC proteins and caused an accumulation of acetylated histone and tubulin following cell treatment. The versatility of the probes has been demonstrated by their ability to photoaffinity modify HDAC targets in vitro. An affinity enrichment probe was used in conjunction with mass spectrometry proteomics to isolate HDACs and their interacting proteins in a native proteome. The performance of the probes in recombinant versus cell-based systems highlights issues for the development of chemoproteomic technologies targeting class IIa HDACs in particular.

Graphical abstract: Design and development of histone deacetylase (HDAC) chemical probes for cell-based profiling

Supplementary files

Article information

Article type
Paper
Submitted
10 feb 2016
Accepted
21 mar 2016
First published
29 mar 2016

Mol. BioSyst., 2016,12, 1781-1789

Design and development of histone deacetylase (HDAC) chemical probes for cell-based profiling

V. E. Albrow, R. L. Grimley, J. Clulow, C. R. Rose, J. Sun, J. S. Warmus, E. W. Tate, L. H. Jones and R. I. Storer, Mol. BioSyst., 2016, 12, 1781 DOI: 10.1039/C6MB00109B

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements