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

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.

Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension

“…FAM60A/SINHCAF is part of the SIN3A-HDAC complex, a master transcriptional repressor that is required for a complete response to hypoxia. 61 FAM60A/SINHCAF specifically represses HIF2a mRNA and protein expression by interacting with the TF SP1 and recruitment of HDAC1 to the HIF2a promoter. 62 HDAC7 is a class IIa histone deacetylase with a well described role in regulating angiogenesis.…”

A single short reprogramming early in life improves fitness and increases lifespan in old age

“…Interestingly, GO analysis with the 70 genes associated to this 2641 differentially methylated sites, revealed that 26 genes and miRNAs are related to aging (Supplementary Table 1). Interestingly, some of them are directly or indirectly involved in chromatin remodeling (25), DNA damage response pathways (26), stress resistance (27) and longevity (28) and some miRNAs like mir125b-1 are preferentially expressed by skin stem cells regulating self-renewal and differentiation (29). Altogether, these results suggest strongly that our short induction protocol might improve the biological age of the skin through an epigenetically related mechanism.…”

Coregulator Sin3a Promotes Postnatal Murine β-Cell Fitness by Regulating Genes in Ca2+ Homeostasis, Cell Survival, Vesicle Biosynthesis, Glucose Metabolism, and Stress Response

“…Consequently, Sin3a was reported to be required for the development and/or survival of embryonic stem (ES) cells (11,12), muscle cells (13), male germ cells (14), lung progenitors (15), and some skin cells (16). In addition, gene expression and protein-DNA interaction studies showed that Sin3a could directly regulate molecules involved in cell proliferation, survival, metabolism, and stress responses (7,17,18), yet how Sin3a functions in postnatal organs has not been examined.…”