RT Journal Article
SR Electronic
T1 The SIN3A histone deacetylase complex is required for a complete transcriptional response to hypoxia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 182691
DO 10.1101/182691
A1 Maria Tiana
A1 Barbara Acosta-Iborra
A1 Laura Puente-Santamaría
A1 Pablo Hernansanz-Agustin
A1 Rebecca Worsley-Hunt
A1 Norma Masson
A1 Francisco García-Rio
A1 David Mole
A1 Peter Ratcliffe
A1 Wyeth W. Wasserman
A1 Benilde Jimenez
A1 Luis del Peso
YR 2017
UL http://biorxiv.org/content/early/2017/09/05/182691.abstract
AB 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.