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Nucleic Acids Res. 2018 Jan 9;46(1):120-133. doi: 10.1093/nar/gkx951.

The SIN3A histone deacetylase complex is required for a complete transcriptional response to hypoxia.

Author information

1
Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), 28029 Madrid, Spain.
2
IdiPaz, Instituto de Investigación Sanitaria del Hospital Universitario La Paz, 28029 Madrid, Spain.
3
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28029 Madrid, Spain.
4
Servicio Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria del hospital de La Princesa, 28006 Madrid, Spain.
5
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia Vancouver, British Columbia V5Z 4H4, Canada.
6
Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
7
Servicio de Neumología, Hospital Universitario La Paz, Instituto de Investigación Sanitaria del hospital de La Paz, 28029 Madrid, Spain.
8
Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK.

Abstract

Cells adapt to environmental changes, including fluctuations in oxygen levels, through the induction of specific gene expression programs. To identify genes regulated by hypoxia at the transcriptional level, we pulse-labeled HUVEC cells with 4-thiouridine and sequenced nascent transcripts. Then, we searched genome-wide binding profiles from the ENCODE project for factors that correlated with changes in transcription and identified binding of several components of the Sin3A co-repressor complex, including SIN3A, SAP30 and HDAC1/2, proximal to genes repressed by hypoxia. SIN3A interference revealed that it participates in the downregulation of 75% of the hypoxia-repressed genes in endothelial cells. Unexpectedly, it also blunted the induction of 47% of the upregulated genes, suggesting a role for this corepressor in gene induction. In agreement, ChIP-seq experiments showed that SIN3A preferentially localizes to the promoter region of actively transcribed genes and that SIN3A signal was enriched in hypoxia-repressed genes, prior exposure to the stimulus. Importantly, SINA3 occupancy was not altered by hypoxia in spite of changes in H3K27ac signal. In summary, our results reveal a prominent role for SIN3A in the transcriptional response to hypoxia and suggest a model where modulation of the associated histone deacetylase activity, rather than its recruitment, determines the transcriptional output.

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