Multi-dimensional histone methylations for coordinated regulation of gene expression under hypoxia

Lee, Seongyeol; Lee, Jieon; Chae, Sehyun; Moon, Yunwon; Lee, Ho-Youl; Park, Bongju; Yang, Eun Gyeong; Hwang, Daehee; Park, Hyunsung

doi:10.1093/nar/gkx747

Cited by 21 publications

(31 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1D). Consistent with prior reports (20)(21)(22)(23)(24)(25)(26)(27)(28), hypoxia promoted the hypermethylation (me2/me3 states) of H3K4, H3K9, and H3K27 ( Fig. 1D).…”

Section: Main Textsupporting

confidence: 92%

See 1 more Smart Citation

The UTX Tumor Suppressor Directly Senses Oxygen to Control Chromatin and Cell Fate

Chakraborty

Laukka

Myllykoski

et al. 2019

Preprint

View full text Add to dashboard Cite

Mammalian cells express multiple 2-oxoglutarate (OG)-dependent dioxygenases, including many chromatin regulators. The oxygen affinities, and hence oxygen sensing capabilities, of the 2-oxoglutarate (OG)-dependent dioxygenases reported to date vary widely. Hypoxia can affect chromatin, but whether this reflects a direct effect on chromatin-modifying dioxygenases, or indirect effects caused by the hypoxic-induction of the HIF transcription factor or the endogenous 2-OG competitor 2-hydroxyglutarate (2-HG), is unclear. Here we report that hypoxia induces a HIF-and 2-HG-independent histone modification signature consistent with KDM inactivation. We also show that the H3K27 histone demethylase KDM6A (also called UTX), but not its paralog KDM6B, is oxygen-sensitive. KDM6A loss, like hypoxia, prevented H3K27me3 erasure and blocked differentiation. Conversely, restoring H3K27me3 homeostasis in hypoxic cells reversed these effects. Therefore, oxygen directly affects chromatin regulators to control cell fate.

show abstract

“…1D). Consistent with prior reports (20)(21)(22)(23)(24)(25)(26)(27)(28), hypoxia promoted the hypermethylation (me2/me3 states) of H3K4, H3K9, and H3K27 ( Fig. 1D).…”

Section: Main Textsupporting

confidence: 92%

“…In support of the latter, some KDMs have been reported to have low oxygen affinities in vitro (19)(20)(21). Finally, hypoxia promotes the accumulation of hypermethylated histones (20)(21)(22)(23)(24)(25)(26)(27)(28).…”

Section: Main Textmentioning

confidence: 85%

The UTX Tumor Suppressor Directly Senses Oxygen to Control Chromatin and Cell Fate

Chakraborty

Laukka

Myllykoski

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…ChIP analyses were performed as described previously 38 . FAIRE analyses were performed using ChIP lysates (30 μg chromatin) as described previously 39 .…”

Section: Methodsmentioning

confidence: 99%

Wnt3a disrupts GR-TEAD4-PPARγ2 positive circuits and cytoskeletal rearrangement in a β-catenin-dependent manner during early adipogenesis

et al. 2019

Self Cite

View full text Add to dashboard Cite

Adipogenesis is a process which induces or represses many genes in a way to drive irreversible changes of cell phenotypes; lipid accumulation, round cell-shape, secreting many adipokines. As a master transcription factor (TF), PPARγ2 induces several target genes to orchestrate these adipogenic changes. Thus induction of Pparg2 gene is tightly regulated by many adipogenic and also anti-adipogenic factors. Four hours after the treatment of adipogenic hormones, more than fifteen TFs including glucocorticoid receptor (GR), C/EBPβ and AP-1 cooperatively bind the promoter of Pparg2 gene covering 400 bps, termed “hotspot”. In this study, we show that TEA domain family transcription factor (TEAD)4 reinforces occupancy of both GR and C/EBPβ on the hotspot of Pparg2 during early adipogenesis. Our findings that TEAD4 requires GR for its expression and for the ability to bind its own promoter and the hotspot region of Pparg2 gene indicate that GR is a common component of two positive circuits, which regulates the expression of both Tead4 and Pparg2. Wnt3a disrupts these mutually related positive circuits by limiting the nuclear location of GR in a β-catenin dependent manner. The antagonistic effects of β-catenin extend to cytoskeletal remodeling during the early phase of adipogenesis. GR is necessary for the rearrangements of both cytoskeleton and chromatin of Pparg2, whereas Wnt3a inhibits both processes in a β-catenin-dependent manner. Our results suggest that hotspot formation during early adipogenesis is related to cytoskeletal remodeling, which is regulated by the antagonistic action of GR and β-catenin, and that Wnt3a reinforces β-catenin function.

show abstract

“…Indeed, with prolonged hypoxia, HIF-levels fall, although remain above normoxic levels. Similarly, many of the JmjC KDMs and TET enzymes, as well as DNA methyltransferases (DNMTs), have been found to be direct transcriptional targets of HIF (Table 2) [29,40,[67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82]. In each case, induction of KDMs by HIF will act to increase demethylase activity, thereby reducing methylation of the targeted mark.…”

Section: Oxygen-dependent Changes In Enzyme Abundancementioning

confidence: 99%

Hypoxic Regulation of Gene Transcription and Chromatin: Cause and Effect

Kindrick

Mole

2020

IJMS

View full text Add to dashboard Cite

Cellular responses to low oxygen (hypoxia) are fundamental to normal physiology and to the pathology of many common diseases. Hypoxia-inducible factor (HIF) is central to this by enhancing the transcriptional activity of many hundreds of genes. The cellular response to HIF is cell-type-specific and is largely governed by the pre-existing epigenetic landscape. Prior to activation, HIF-binding sites and the promoters of HIF-target genes are already accessible, in contact with each other through chromatin looping and display markers of activity. However, hypoxia also modulates the epigenetic environment, both in parallel to and as a consequence of HIF activation. This occurs through a combination of oxygen-sensitive changes in enzyme activity, transcriptional activation of epigenetic modifiers, and localized recruitment to chromatin by HIF and activated RNApol2. These hypoxic changes in the chromatin environment may both contribute to and occur as a consequence of transcriptional regulation. Nevertheless, they have the capacity to both modulate and extend the transcriptional response to hypoxia.

show abstract

Multi-dimensional histone methylations for coordinated regulation of gene expression under hypoxia

Cited by 21 publications

References 70 publications

The UTX Tumor Suppressor Directly Senses Oxygen to Control Chromatin and Cell Fate

The UTX Tumor Suppressor Directly Senses Oxygen to Control Chromatin and Cell Fate

Wnt3a disrupts GR-TEAD4-PPARγ2 positive circuits and cytoskeletal rearrangement in a β-catenin-dependent manner during early adipogenesis

Hypoxic Regulation of Gene Transcription and Chromatin: Cause and Effect

Contact Info

Product

Resources

About