Epigenetic repression of LEDGF during UVB exposure by recruitment of SUV39H1 and HDAC1 to the Sp1-responsive elements within LEDGF promoter CpG island

Bhargavan, Biju; Chhunchha, Bhavana; Fatma, Nigar; Kubo, Eri; Kumar, Anil; Singh, D. P.

doi:10.4161/epi.23861

Cited by 12 publications

(25 citation statements)

References 72 publications

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“…A number of target genes of FGF2 and TGFβ have been identified whose expression is activated by them, some of which are overly stimulated and implicated in EMT process including αSMA, fibronectin and Tpms, and thereby PCO formation . More recently, our group identified modulation in expression of Tpms, specifically high molecular weight Tm isoforms from Tpm1 and Tpm2 genes, in a rodent model of PCO and in LECs obtained from cataractous humans of various ages . We previously reported expression of Tpm1/2 was minimal in rat LECs, and expression of Tpm1/2 that increased selectively during EMT was linked to fibrosis in PCO .…”

Section: Introductionmentioning

confidence: 97%

“…More recently, our group identified modulation in expression of Tpms, specifically high molecular weight Tm isoforms from Tpm1 and Tpm2 genes, in a rodent model of PCO and in LECs obtained from cataractous humans of various ages . We previously reported expression of Tpm1/2 was minimal in rat LECs, and expression of Tpm1/2 that increased selectively during EMT was linked to fibrosis in PCO . Other cellular abnormalities, particularly in aberrant expression of cytoskeleton and ECM proteins, are induced because of overshooting of cellular signalling mediated by reactive oxygen species (ROS) .…”

Section: Introductionmentioning

confidence: 99%

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FGF2 antagonizes aberrant TGFβ regulation of tropomyosin: role for posterior capsule opacity

Kubo

Shibata

et al. 2016

J Cellular Molecular Medi

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Transforming growth factor (TGF) β2 and fibroblast growth factor (FGF) 2 are involved in regulation of posterior capsule opacification (PCO) and other processes of epithelial–mesenchymal transition (EMT) such as cancer progression, wound healing and tissue fibrosis as well as normal embryonic development. We previously used an in vivo rodent PCO model to show the expression of tropomyosin (Tpm) 1/2 was aberrantly up‐regulated in remodelling the actin cytoskeleton during EMT. In this in vitro study, we show the Tpms family of cytoskeleton proteins are involved in regulating and stabilizing actin microfilaments (F‐actin) and are induced by TGFβ2 during EMT in lens epithelial cells (LECs). Importantly, we found TGFβ2 and FGF2 played contrasting roles. Stress fibre formation and up‐regulation of α‐smooth muscle actin (αSMA) induced by TGFβ2 could be reversed by Tpm1/2 knock‐down by siRNA. Expression of Tpm1/2 and stress fibre formation induced by TGFβ2 could be reversed by FGF2. Furthermore, FGF2 delivery to TGFβ‐treated LECs perturbed EMT by reactivating the mitogen‐activated protein kinase (MAPK)/ extracellular signal‐regulated kinase (ERK) pathway and subsequently enhanced EMT. Conversely, MEK inhibitor (PD98059) abated the FGF2‐mediated Tpm1/2 and αSMA suppression. However, we found that normal LECs which underwent EMT showed enhanced migration in response to combined TGFβ and FGF2 stimulation. These findings may help clarify the mechanism reprogramming the actin cytoskeleton during morphogenetic EMT cell proliferation and fibre regeneration in PCO. We propose that understanding the physiological link between levels of FGF2, Tpm1/2 expression and TGFβs‐driven EMT orchestration may provide clue(s) to develop therapeutic strategies to treat PCO based on Tpm1/2.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

FGF2 antagonizes aberrant TGFβ regulation of tropomyosin: role for posterior capsule opacity

Kubo

Shibata

et al. 2016

J Cellular Molecular Medi

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“…The pathophysiological changes in the lens associated with cataract formation have also been suggested to involve slowly progressing epigenetic changes similar to that in many other aging tissues 53–55. Such a possibility is indicated by disorganization of the chromatin fibers, associated with the formation of cataracts in diabetic mice56 and its prevention by pyruvate.…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane-induced transcription of thioredoxin reductase in lens: possible significance against cataract formation

Varma¹,

Chandrasekaran²,

Ковтун³

2013

OPTH

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PurposeSulforaphane is a phytochemically derived organic isothiocyanate 1-isothiocyanato-4-methylsulfinyl-butane present naturally in crucifers, including broccoli and cauliflower. Biochemically, it has been reported to induce the transcription of several antioxidant enzymes. Since such enzymes have been implicated in preventing cataract formation triggered by the intraocular generation of oxy-radical species, the purpose of this investigation was to examine whether it could induce the formation of antioxidant enzymes in the eye lens. Thioredoxin reductase (TrxR) was used as the target of such induction.MethodsMice lenses were cultured for an overnight period of 17 hours in medium 199 fortified with 10% fetal calf serum. Incubation was conducted in the absence and presence of sulforaphane (5 μM). Subsequently, the lenses were homogenized in phosphate-buffered saline (PBS), followed by centrifugation. TrxR activity was determined in the supernatant by measuring the nicotinamide adenine dinucleotide phosphate (reduced) (NADPH)-dependent reduction of 5,5′-dithiobis-2-nitrobenzoic acid (DTNB). Non-specific reduction of DTNB was corrected for by conducting parallel determinations in the presence of aurothiomalate. The reduction of DTNB was followed spectrophotometrically at 410 nm.ResultsThe activity of TrxR in the lenses incubated with sulforaphane was found to be elevated to 18 times of that observed in lenses incubated without sulforaphane. It was also noticeably higher in the lenses incubated without sulforaphane than in the un-incubated fresh lenses. However, this increase was much lower than that observed for lenses incubated with sulforaphane.ConclusionSulforaphane has been found to enhance TrxR activity in the mouse lens in culture. In view of the protective effect of the antioxidant enzymes and certain nutrients against cataract formation, the findings suggest that it would, by virtue of its ability to enhance the activity of such enzymes, prevent the tissue against oxidative stress that leads to cataract formation. Additional studies with the activities of other antioxidant enzymes such as quinone oxidoreductase and the levels of Nrf2 are in progress.

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“…Also, the lens epithelial-derived growth factor, LEDGF is expressed by lens epithelial cells, upregulates heat shock proteins and β-crystallins, and responds to environmental stress. LEDGF is an oncogene, and its expression is regulated by a promoter CpG island methylation (Bhargavan et al, 2013; Shinohara et al, 2002). Histone modification is also known to regulate the LEDGF response to UV damage, one of the environmental exposures that lead to ARCs formation (Bhargavan et al, 2013).…”

Section: Regulation Of Dna Methylationmentioning

confidence: 99%

“…LEDGF is an oncogene, and its expression is regulated by a promoter CpG island methylation (Bhargavan et al, 2013; Shinohara et al, 2002). Histone modification is also known to regulate the LEDGF response to UV damage, one of the environmental exposures that lead to ARCs formation (Bhargavan et al, 2013). DNA damage is an additional consequence of oxidative stress, and there are several reports have demonstrated the association between DNA repair genes with ARCs formation.…”

Section: Regulation Of Dna Methylationmentioning

confidence: 99%

Age-related cataracts: Role of unfolded protein response, Ca 2+ mobilization, epigenetic DNA modifications, and loss of Nrf2/Keap1 dependent cytoprotection

Periyasamy

Shinohara

2017

Progress in Retinal and Eye Research

114

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Age-related cataracts are closely associated with lens chronological aging, oxidation, calcium imbalance, hydration and crystallin modifications. Accumulating evidence indicates that misfolded proteins are generated in the endoplasmic reticulum (ER) by most cataractogenic stresses. To eliminate misfolded proteins from cells before they can induce senescence, the cells activate a clean-up machinery called the ER stress/unfolded protein response (UPR). The UPR also activates the nuclear factor- erythroid-2-related factor 2 (Nrf2), a central transcriptional factor for cytoprotection against stress. Nrf2 activates nearly 600 cytoprotective target genes. However, if ER stress reaches critically high levels, the UPR activates destructive outputs to trigger programmed cell death. The UPR activates mobilization of ER-Ca2+ to the cytoplasm and results in activation of Ca2+-dependent proteases to cleave various enzymes and proteins which cause the loss of normal lens function. The UPR also enhances the overproduction of reactive oxygen species (ROS), which damage lens constituents and induce failure of the Nrf2 dependent cytoprotection. Kelch-like ECH-associated protein 1 (Keap1) is an oxygen sensor protein and regulates the levels of Nrf2 by the proteasomal degradation. A significant loss of DNA methylation in diabetic cataracts was found in the Keap1 promoter, which overexpresses the Keap1 protein. Overexpressed Keap1 significantly decreases the levels of Nrf2. Lower levels of Nrf2 induces loss of the redox balance toward to oxidative stress thereby leading to failure of lens cytoprotection. Here, this review summarizes the overall view of ER stress, increases in Ca2+ levels, protein cleavage, and loss of the well-established stress protection in somatic lens cells.

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Epigenetic repression of LEDGF during UVB exposure by recruitment of SUV39H1 and HDAC1 to the Sp1-responsive elements within LEDGF promoter CpG island

Cited by 12 publications

References 72 publications

FGF2 antagonizes aberrant TGFβ regulation of tropomyosin: role for posterior capsule opacity

FGF2 antagonizes aberrant TGFβ regulation of tropomyosin: role for posterior capsule opacity

Sulforaphane-induced transcription of thioredoxin reductase in lens: possible significance against cataract formation

Age-related cataracts: Role of unfolded protein response, Ca 2+ mobilization, epigenetic DNA modifications, and loss of Nrf2/Keap1 dependent cytoprotection

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