Hypoxia and Chromatin: A Focus on Transcriptional Repression Mechanisms

Abstract

Hypoxia or reduced oxygen availability has been studied extensively for its ability to activate specific genes. Hypoxia-induced gene expression is mediated by the HIF transcription factors, but not exclusively so. Despite the extensive knowledge about how hypoxia activates genes, much less is known about how hypoxia promotes gene repression. In this review, we discuss the potential mechanisms underlying hypoxia-induced transcriptional repression responses. We highlight HIF-dependent and independent mechanisms as well as the potential roles of dioxygenases with functions at the nucleosome and DNA level. Lastly, we discuss recent evidence regarding the involvement of transcriptional repressor complexes in hypoxia.

Keywords: HIF; JmjC; chromatin; histone methylation; hypoxia; repressor Complexes; transcriptional repression.

Figure 1

Chromatin structure. Simplified linear diagram of chromatin highlighting the main mechanisms by which chromatin structure is regulated. Chromatin Remodeller Complex (CRC), post translational modification (PTM), and non-coding RNAs, (ncRNAs).

Figure 2

Mammalian Chromatin remodeler complexes. Chromatin Remodeler Complexes (CRCs) from the four subfamilies of CRCs based on ATPase domains are shown. (A) SWItch/Sucrose Non-Fermentable (SWI/SNF), (B) imitation SWI (ISWI), (C) inositol-Requiring 80/Sick with RSC (INO80/SWR), and (D) Chromodomain Helicase DNA-binding CHD (CHD). Rectangles represent ATPase domain. Brahma (BRM) BRM Related Gene 1 (BRG1), BRG1/BRM Associated Factor (BAF), Polybromo Associated BAF Complex (PBAF), Snf2 Related CREBBP Activator Protein (SRCAP), Tat Interacting Protein 60 (TIP60), Nucleosome Remodeling Deacetylase (NuRD), Chromatin Accessibility Complex (CHRAC), Remodeling And Spacing Factor (RSF), Nucleolar Remodeling Complex, Cat Eye Syndrome Chromosome Region Candidate 2 (CERC2), CECR2 Containing Remodeling Factor (CERF), Nucleosome Remodeling Factor (NURF), B-Cell CLL/Lymphoma (BCL), Bromodomain Containing (BRD), Polybromo 1 (PBRM1), RuvB Like AAA ATPase (RUVBL)(RVB), Actin related protein (ARP), Ubiquitin C-Terminal Hydrolase L5 (UCH37 Microspherule Protein 1 (MCRS1), Nuclear Factor Kappa B Subunit (NF κβ), DNA Methyltransferase 1 Associated Protein 1 (DMAP1), Glioma-Amplified Sequence 41 (GAS41), Vacuolar Protein Sorting 72 (VPS72), Zinc Finger HIT-Type Containing 1 (ZNHIT1), H2A Histone Family Member Z (H2AZ), Transformation/Transcription Domain Associated Protein (TRRAP), MORF-Related Gene 15 Protein (MRG15), MRG Domain Binding Protein (MRGBP), Esa1 Associated Factor 6 (EAF6), Inhibitor Of Growth Family Member 3 (ING3), Histone Deacetylase, (HDAC), Metastasis Associated (MTA), Retinoblastoma-Binding Protein (RBAP), ATP-Dependent Chromatin Assembly Factor 1 (ACF1), Sucrose Nonfermenting Protein 2 Homolog (SNF2H), Sucrose Nonfermenting 2-Like Protein 1 (SNF2L), Williams Syndrome Transcription Factor (WSTF), and Bromodomain PHD Finger Transcription Factor (BPTF).

Figure 3

Dynamics of DNA methylation. DNA methylation is performed by DNA Methyl Transferases (DNMT) enzymes and removed by Ten-Eleven-Translocation (TET) enzymes. DNMTs target areas of unmethylated H3K4 and trimethylated H3K36 or di/trimethylated H3K9.

Figure 4

Mechanisms of hypoxic gene repression in the context of chromatin structure. Hypoxia Inducible Factor (HIF), Repressor Element 1-Silencing Transcription Factor (REST), SIN3 Transcription Regulator Family Member A (SIN3A), Histone Deacetylase, (HDAC), G9α Like Protein 1 (GPL), Suppressor of Variegation 3–9 Homolog (SUV39H), SET Domain Bifurcated 1 (SETDB1), Chromatin Remodeller Complex (CRC), Jumoni C (JmjC), DNA Methyl Transferase (DNMT), Ten-Eleven-Translocation (TET), and Lysine Specific Demethylase 1 (LSD1).