SWI/SNF Regulates the Cellular Response to Hypoxia

Abstract

Hypoxia induces a variety of cellular responses such as cell cycle arrest, apoptosis, and autophagy. Most of these responses are mediated by the hypoxia-inducible factor-1␣. To induce target genes, hypoxia-inducible factor-1␣ requires a chromatin environment conducive to allow binding to specific sequences. Here, we have studied the role of the chromatin-remodeling complex SWI/SNF in the cellular response to hypoxia. We find that SWI/SNF is required for several of the cellular responses induced by hypoxia. Surprisingly, hypoxia-inducible factor-1␣ is a direct target of the SWI/SNF chromatin-remodeling complex. SWI/SNF components are found associated with the hypoxia-inducible factor-1␣ promoter and modulation of SWI/ SNF levels results in pronounced changes in hypoxia-inducible factor-1␣ expression and its ability to transactivate target genes. Furthermore, impairment of SWI/SNF function renders cells resistant to hypoxia-induced cell cycle arrest. These results reveal a previously uncharacterized dependence of hypoxia signaling on the SWI/SNF complex and demonstrate a new level of control over the hypoxia-inducible factor-1␣ system.

Epigenetics: The epicenter of the hypoxic response

“…21 SWI/SNF, which can play a role in both enhancement and repression of gene transcription, was shown to directly bind the HIF-1α promoter and the BAF57 subunit of SWI/SNF was essential for hypoxia induced HIF-1α expression. Kenneth et al also revealed that the SWI/SNF chromatin remodeling complex was required for hypoxia-induced cell cycle arrest.…”

Hypoxia-induced autophagy contributes to the chemoresistance of hepatocellular carcinoma cells

“…It has been reported that hypoxia induces cell cycle arrest, 38,39 and cell cycle arrest is one of the important factors for chemoresistance of cancer cells. 39,45 However, in our study, the cell cycle distribution differences between cells under normoxia and hypoxia were not meaningful by statistical analysis (Fig.…”

“…But how does it work? As hypoxia can induce cell cycle arrest, 38,39 whether the attenuated chemosensitivity under hypoxia attributes to the blocked cell cycle, especially in G 0 /G 1 . Contrary to our expectation, cell cycle analysis by flow cytometric measurement of DNA content revealed that, though there was a difference in cell cycle distribution between cells under hypoxia and normoxia, it is not meaningful by statistical analysis (Fig.…”

Neurogenetic Aspects of Perinatal Hypoxic-Ischemic Affections of the Central Nervous System

“…HIF-1␣ связывается с чув-ствительными элементами гипоксии в промотерных и уси-ливающих регионах генов-мишеней, способствуя образо-ванию гипоксически индуцируемого фенотипа [56]. Однако, в свою очередь, экспрессия HIF сама может быть пред-метом эпигенетических регуляций, причем всех механиз-мов (метилирования/деметилирования ДНК, модификации гистонов и микроРНК), что было доказано целым рядом последних исследований [57][58][59][60][61]. Кроме того, помимо HIF имеются и другие факторы, вовлеченные в гипоксическую эпигенетическую регуляцию и формирование чувствитель-ного к гипоксии фенотипа.…”