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Suberoylanilide hydroxamic acid induces limited changes in the transcriptome of primary CD4(+) T cells

Suberoylanilide hydroxamic acid induces limited changes in the transcriptome of primary CD4(+) T cells
Suberoylanilide hydroxamic acid induces limited changes in the transcriptome of primary CD4(+) T cells
OBJECTIVE: To assess the off-target effects of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) in human primary CD4 T cells.

DESIGN: A pharmacologically relevant concentration (340 nmol/l) of SAHA was shown to significantly increase histone hyperacetylation by 24 h and this length of treatment was selected to determine its impact on gene expression in primary CD4 T cells.

METHODS: Illumina Beadchips for microarray gene expression analysis were used to analyze differential gene expression between cells treated or not with SAHA with a paired analysis using multivariate permutation tests. Gene ontology, biological pathway and protein interaction network analyses were used to identify the higher order biological processes affected by SAHA treatment.

RESULTS: Modest modulation by SAHA was observed for 1847 genes with 80% confidence level of no more than 10% false positives. A thousand genes were upregulated by SAHA and 847 downregulated. Pathways and gene ontologies overrepresented in the list of differentially expressed genes included Glycolysis/Gluconeogenesis, tRNA Modification, and the Histone Acetyltransferase Complex. Protein interaction network analysis revealed that transcription factor c-Myc, which was downregulated by SAHA treatment at the mRNA level, interacts with a number of SAHA-responsive genes.

CONCLUSIONS: The effects on transcription by SAHA were sufficiently modest to support trials to activate HIV replication as part of an eradication strategy. SAHA did not appear to modulate proliferative or apoptotic processes to a great extent, which might impact the ability of patients to eradicate the virus reservoir following activation by HDACi treatment.
29-37
Beliakova-Bethell, N.
5919f4d5-b2a8-4d9a-a3be-d0a78d8485b1
Zhang, J.X.
9c53aa66-c108-4b31-97ae-4b7d05a91571
Singhania, A.
9a5f2c6b-fc46-4223-bcae-de70bf14da6b
Lee, V.
6f929021-0f17-44cc-962b-50d036459356
Terry, V.H.
a0905638-d89f-4785-b1a5-c7f7d670726f
Richman, D.D.
1d5f38e4-c778-4b0b-b542-9d1160e63041
Spina, C.A.
644b537b-d0f2-4c09-a43e-8b54f74c68a9
Woelk, C.H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
Beliakova-Bethell, N.
5919f4d5-b2a8-4d9a-a3be-d0a78d8485b1
Zhang, J.X.
9c53aa66-c108-4b31-97ae-4b7d05a91571
Singhania, A.
9a5f2c6b-fc46-4223-bcae-de70bf14da6b
Lee, V.
6f929021-0f17-44cc-962b-50d036459356
Terry, V.H.
a0905638-d89f-4785-b1a5-c7f7d670726f
Richman, D.D.
1d5f38e4-c778-4b0b-b542-9d1160e63041
Spina, C.A.
644b537b-d0f2-4c09-a43e-8b54f74c68a9
Woelk, C.H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d

Beliakova-Bethell, N., Zhang, J.X., Singhania, A., Lee, V., Terry, V.H., Richman, D.D., Spina, C.A. and Woelk, C.H. (2013) Suberoylanilide hydroxamic acid induces limited changes in the transcriptome of primary CD4(+) T cells. AIDS, 27 (1), 29-37. (doi:10.1097/QAD.0b013e32835b3e26). (PMID:23221426)

Record type: Article

Abstract

OBJECTIVE: To assess the off-target effects of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) in human primary CD4 T cells.

DESIGN: A pharmacologically relevant concentration (340 nmol/l) of SAHA was shown to significantly increase histone hyperacetylation by 24 h and this length of treatment was selected to determine its impact on gene expression in primary CD4 T cells.

METHODS: Illumina Beadchips for microarray gene expression analysis were used to analyze differential gene expression between cells treated or not with SAHA with a paired analysis using multivariate permutation tests. Gene ontology, biological pathway and protein interaction network analyses were used to identify the higher order biological processes affected by SAHA treatment.

RESULTS: Modest modulation by SAHA was observed for 1847 genes with 80% confidence level of no more than 10% false positives. A thousand genes were upregulated by SAHA and 847 downregulated. Pathways and gene ontologies overrepresented in the list of differentially expressed genes included Glycolysis/Gluconeogenesis, tRNA Modification, and the Histone Acetyltransferase Complex. Protein interaction network analysis revealed that transcription factor c-Myc, which was downregulated by SAHA treatment at the mRNA level, interacts with a number of SAHA-responsive genes.

CONCLUSIONS: The effects on transcription by SAHA were sufficiently modest to support trials to activate HIV replication as part of an eradication strategy. SAHA did not appear to modulate proliferative or apoptotic processes to a great extent, which might impact the ability of patients to eradicate the virus reservoir following activation by HDACi treatment.

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More information

Published date: 2 January 2013
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 350570
URI: https://eprints.soton.ac.uk/id/eprint/350570
PURE UUID: 404ec1c2-c6fe-48c6-82b1-afa3cff530a9

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Date deposited: 04 Apr 2013 11:02
Last modified: 18 Jul 2017 04:33

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