Published online before print November 2, 2006, doi: 10.1161/01.RES.0000251744.06138.50
© 2006 American Heart Association, Inc.
Molecular Medicine |
Transcriptional Silencing of the Death Gene BNIP3 by Cooperative Action of NF-
B and Histone Deacetylase 1 in Ventricular Myocytes
From the Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, departments of Physiology (T.Z., M.R., N.Y., D.B.), Pharmacology and Therapeutics (L.A.K., J.S.); Manitoba Cancer Treatment Centre (J.R.D.), Faculty of Medicine University of Manitoba, Winnipeg, Manitoba, Canada.
Correspondence to Dr Lorrie A. Kirshenbaum, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre Rm. 3016, 351 Taché Avenue, Winnipeg, Manitoba, Canada, R2H 2A6. E-mail Lorrie{at}sbrc.ca
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Abstract |
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Earlier we identified a survival role for NF-
B in ventricular myocytes, however, the underlying mechanism was undefined. In this report we provide new mechanistic evidence that the hypoxia-inducible death factor BNIP3 is transcriptionally silenced by NF-B through a mechanism that involves the cooperative actions of HDAC1. Activation of the NF-B signaling pathway in ventricular myocytes suppressed basal and hypoxia-inducible BNIP3 gene activity. Basal Bnip3 gene expression was increased in cells derived from p65–/– deficient mice. The histone deacetylase (HDAC) inhibitor Trichostatin A (TSA 10 nM) suppressed the inhibitory actions of NF-B on Bnip3 gene transcription. Basal and hypoxia- induced Bnip3 transcription was repressed by wild type but not a catalytically inactive mutant of HDAC1. Immunoprecipitation assays verified interaction of HDAC1 with wild type p65 NF-B and mutations of p65 defective for transactivation in ventricular myocytes. Deletion analysis revealed canonical NF-B elements within the Bnip3 promoter to be important for repression of Bnip3 gene expression by HDAC1. Further, the ability of HDAC1 to repress Bnip3 gene transcription was lost in cells derived from p65–/– deficient mice but was restored by repletion of p65 NF-B into p65–/– cells. Mutations of p65 NF-B defective for DNA binding but not for transactivation abrogated the inhibitory actions of HDAC1 on the Bnip3 gene transcription. Together, our findings provide new mechanistic insight into the cytoprotective actions conferred by NF-B that extend to the active transcriptional repression of the death factor Bnip3 through a mechanism that is mutually dependent on HDAC-1.
Key Words: ventricular myocytes • apoptosis • NF-B • cell culture
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Nuclear Factor-
B (NF-B) regulates a wide range of cellular processes including T-cell maturation, inflammation, and cell survival. In cells, NF-B exists as a heterodimer comprised of p50 and p65 KDa protein subunits. In absence of activating signals, NF-B is sequestered in the cytoplasm by the inhibitor protein IB
. Biological signals that lead to NF-B activation involve the phosphorylation dependent degradation of IB mediated by the IKK signaling complex. In particular, IKKß is the principle kinase responsible for NF-B activation. IKKß phosphorylates IB at critical serine residues 32 and 36 resulting in degradation of IB by the proteasome.1,2 Ostensibly, the phosphorylation dependent loss of IB activity permits NF-B to translocate to the nucleus and affect gene transcription.3 Despite this well accepted and proven model for signal induced NF-B activity, there are several reports documenting the presence of NF-B in the nucleus of nonstimulated cells.4,5 The significance of this finding is unknown, but raises the intriguing possibility that the basal activity of certain promoters may be regulated by NF-B. In this context, much of the known biological actions of NF-B including its antiapoptosis properties have been ascribed to its well known and proven role as a transcriptional activator.6,7 However, recent data from our laboratory as well as others suggest that NF-B may also act as a transcriptional repressor.5,8 The biological significance of this feature and its relation to cell death is unknown and has not been formally tested. Gene transcription is a dynamic process governed by the extent and level of histone activity at a given promoter. Among the best studied histone modifications known to influence gene transcription is histone acetylation, which is governed by the balanced actions of histone acetylases and deacetylases (HDACs).9 The class I HDACs which include HDAC 1, HDAC 2, HDAC 3, and HDAC 8 are recruited to DNA as part of a large multiprotein repressor complex comprised of Sin3 or Mi-2-NuRD proteins.10,11 One paradigm purports that HDACs inhibit gene transcription by deacetylating histone core proteins,12 this compacts the nucleosome sterically impairing access of transcription factors to DNA reviewed in [13,9,11]. In addition to histone modification, HDACs can reportedly influence gene transcription by modifying nonhistone DNA binding factors.14 Indeed, the ability of HDACs to impair gene transcription by interacting with sequence specific transcription factors has been reported.5,15–17
Previously we showed that IKKß-mediated NF-B activation was sufficient to suppress hypoxia-induced mitochondrial perturbations and cell death of ventricular myocytes.18 We further demonstrated that NF-B averted cell death by transcriptionally silencing the mitochondrial death factor Bnip3.8 In this report we provide new evidence that NF-B mediated repression of BNIP3 occurs through a mechanism that involves the recruitment and deacetylase activity of HDAC-1. We further demonstrate the inhibitory actions of HDAC1 are contingent on the DNA binding properties of p65 NF-B and mediated through the NF-B elements within the Bnip3 promoter. Our data provide novel evidence that survival signals mediated by NF-B involve the active transcriptional repression of the death factor Bnip3 through cooperative actions of HDAC 1.
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Materials and Methods |
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Cell Culture and Transfection
Postnatal ventricular myocytes from 2-day-old Sprague Dawley rat hearts were isolated and submitted to primary culture as previously described.19,20,21 Myocytes or mouse embryonic fibroblasts (MEF) were transfected with the wild type (WT) 2.3 kBp Bnip3 promoter luciferase reporter (Bnip3 WT) and Bnip3 promoter in which the canonical NF-
B elements (NRE) had been deleted and designated (Bnip3 mt) as previously described.21,19,22,8 Mouse embryonic fibroblasts derived from WT p65 +/+ and p65 –/– mice were generously provided by Dr D. Baltimore.23 Expression plasmids encoding epitope-FLAG-tagged derivatives WT p65 and transactivation defective mutations (p65S529A, p65S36A) were kindly provided by Dr A. Baldwin,24; the p65 NF-B DNA binding mutant (p65Y23E26) designated p65-DB was kindly provided by Dr G. Natoli.25 Eurkaryotic expression plasmids encoding WT histone deacetylase 1 (HDAC1) and catalytically inactive mutant HDAC H141A have been described previously described.26 Cells were transfected with the CMV driven eukaryotic expression vector without complementary DNA insert for all transfection controls. Myocytes were maintained in serum free DMEM for 24 to 48 hours. Data were obtained from at least n=4 independent cultures using replicates of n=3 for each condition tested. Luciferase activity was normalized to ß-galactosidase activity to control for differences in transfection efficiency and data are expressed as relative light units.19,21
Immunoprecipitation and Western Blot
For immunodetection of p65-NF-B and HDAC1 proteins, cardiac myocytes were harvested in 1.0% NP-40, 0.5% sodium dodecyl sulfate, 150 mmol/L NaCl, 50 mmol/L Tris-HCl, pH 7.4, (NP40 buffer). Cell lysates (100 µg) were resolved on a 10% sodium dodecyl sulfate-polyacrylamide gel at 140 V for 4 hours and electrophoretically transferred to polyvinylidiene difluoride membrane PVDF (Roche Diagnostics). For detection of p65 NF-B, the filter was probed with an anti-p65 antibody, clone C20, cat# sc-372 (200 µg/mL Santa Cruz Biotechnology, Calif) in NP-40 lysis buffer, pH 7.4, containing 0.3% Tween-20, 0.1% bovine serum albumin (TBS-Tween). For detection of HDAC1 the filter was probed with anti- HDAC 1 antibody, clone H51, cat # sc-7872 (200 µg/mL Santa Cruz Biotechnology) in TBS-Tween. For detection of p65 NF-B - HDAC1 interactions, lysates from cells transfected with p65-FLAG tagged proteins were incubated with an anti-FLAG M2 antibody (Sigma, Oakville, Ontario, Canada) and immunoprecipitated with protein A-G agarose beads (Pharmacia, New York, NY). Bound proteins were detected by chemiluminescence reaction by enhanced ECL reagents (Amersham, Piscatawy, NJ).
Cell Culture and Hypoxia
Postnatal ventricular myocytes from 1- to 2-day-old Sprague-Dawley rats were subjected to hypoxia for 24 hours in an air-tight chamber under serum free culture conditions continually gassed with 95% N2 to 5% CO2, pO2
10 mm Hg as previously described.8,21,27
Recombinant Adenovirus
Myocytes were infected with adenoviruses encoding WT IKKß (Ad IKKßWT),18 or control adenovirus containing the CMV promoter (Ad CMV) at multiplicity of infection (MOI) of 10 which achieves >90% of gene delivery to ventricular myocytes.28
RNA and Semi-Quantitative RT-PCR
RT-PCR was performed using 0.5 µg of total RNA using the Promega Access RT-PCR System (Promega Corporation, Madison, Wis) on a PTC-100 thermocycler (MJ Research, Inc, Waltham, Mass) for BNIP3 or house keeping control gene L32 respectively; BNIP3: forward 5'-GGGTAGAACTGCACTTCAGCAA-3' and reverse 5'-CCTGTTGGTATCTTGTGGTGT-3'; L32 gene: forward 5'-TAAGCGAAACTGGCGGAAAC-3' reverse 5'-GCTGCTCTTTCTACGATGGCTT-3' RT-PCR products were analyzed by 2% gel electrophoresis.8 Relative band intensity was quantified by fluorescence scanning densitometry and normalized to L32 gene on Storm gel analysis system, (Molecular Dynamics, Sunnyvale, Calif).
Statistical Analysis
Multiple comparisons between groups were determined by ANOVA. Unpaired 2 tailed Students-t test was used to compare mean differences between groups. Differences were considered to be statistically significant to a level of P<0.05. In all cases the data were obtained from at least n=3 to 4 independent myocyte isolations using n=3 replicates for each condition tested.
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Results |
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Previously we identified canonical binding elements for NF-
B in the Bnip3 promoter (base pairs -1075 to -1069) that were found to be crucial for the inhibitory actions of NF-B on Bnip3 gene expression. To begin to assess the underlying mechanisms by which NF-B represses Bnip3 transcription, we focused our attention on the p65 NF-B subunit because the biological properties conferred by NF-B have largely been attributed to the actions of the p65, and our earlier work demonstrated the importance of the p65 for suppressing apoptosis in ventricular myocytes.8,29 We reasoned that NF-B may signal through inhibitory factors to repress Bnip3 gene activity. Because HDACs are a major class of chromatin modifying proteins that can reportedly influence NF-B transcription,5 we tested the possibility that HDAC proteins may be involved in the NF-B mediated repression of Bnip3 gene transcription. For these experiments the effect of trichostatin A (TSA, 10 nM) a known HDAC inhibitor was tested on Bnip3 gene transcription in the presence and absence of p65 NF-B. As shown in Figure 1 (panel A), a 4.0 fold (P<0.01) reduction in Bnip3 gene transcription was observed in cells expressing the p65 NF-B. However, the HDAC inhibitor TSA interfered with the inhibitory actions of p65 on Bnip3 gene transcription. Further, a 2.5-fold increase in basal Bnip3 gene transcription was observed in myocytes in the presence of TSA (Figure 1, panel A). To verify that the derepression of the Bnip3 promoter by TSA was not related to spurious effects or restricted to the Bnip3 luciferase reporter, we examined whether TSA would abrogate the repressive effects of NF-B on the endogenous Bnip3 gene. For these experiments, ventricular myocytes were infected with an adenovirus encoding IKKß as means to activate NF-B. As shown in Figure 1(panel B), a 2.0 fold reduction in endogenous Bnip3 expression was observed in ventricular myocytes expressing IKKß, a finding concordant with our earlier work.8,18 Importantly, the repressive effects of IKKß-mediated NF-B activation on Bnip3 gene transcription were suppressed by TSA, a finding consistent with our Bnip3 transcription data. Collectively, our data support the notion that HDACs may be involved in the transcriptional repression of Bnip3 by NF-B.
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=statistically different from p65; N.S.=not significant.
Our preliminary findings30 and immunoprecipitation experiments in ventricular myocytes revealed the interaction of the p65 subunit of NF-B with only the class I HDAC, HDAC1, (Figure 2, panels A and B). These findings provide cogent evidence that HDAC1 is involved in the transcriptional repression of Bnip3 by p65 NF-B. Therefore, we focused our attention on HDAC1 and tested whether NF-B signals through HDAC1 to repress Bnip3 gene transcription.
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For these experiments, cells were transfected with p65 NF-B in the presence and absence of WT or a catalytically inactive form of HDAC1 (HDAC1 H141A) defective for histone deacetylase activity. As shown in Figure 3 (panel A), WT HDAC1 repressed basal BNIP3 gene transcription by 5.0 fold compared with control cells or cells expressing the catalytically inactive HDAC1 H141A. The inhibitory actions of the p65 NF-B on Bnip3 gene transcription were suppressed in cells expressing the catalytically inactive HDAC 1, Figure 3 (panel B), a finding consistent with the operation of HDAC1 in repression of Bnip3 by NF-B.
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=statistically different from HDAC1; # = statistically different from p65+HDAC1.
To gain further insight into the mechanism underlying the repression of Bnip3 transcription by p65NF-B, we assessed whether the inhibitory actions of HDAC1 on Bnip3 gene transcription were related to and functionally dependent on the p65 NF-B. For these studies we tested the impact of HDAC1 in the presence of WT p65 NF-B and mutations of p65 defective for transactivation.8,5 As shown in Figure 4 (panel A), Bnip3 gene transcription was repressed in cells expressing HDAC1 in the presence of either WT p65 NF-B or mutations of p65 NF-B defective for transactivation, suggesting that repression of Bnip3 gene transcription is related to the deacetylase activity of HDAC1 and not the transactivation potential of p65 NF-B. Further, the p65 NF-B proteins tested were expressed to comparable levels and interacted equivalently with HDAC1 Figure 4, panel B. Importantly, expression of the endogenous HDAC1 protein in cells expressing p65 proteins was comparable to vector transfected control cells, Figure 4 panel C. Because HDACs do not directly bind DNA, we next assessed whether DNA binding properties of p65 NF-B were necessary for the inhibitory effects of HDAC1 on Bnip3 transcription.
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As shown in Figure 4 panel A, the ability of HDAC1 to repress Bnip3 transcription was abrogated in cells expressing a p65 NF-B defective for DNA binding, supporting the notion that the DNA binding properties of p65 are required for repressive effects of HDAC1 on Bnip3 transcription. Furthermore, deletion of the NF-B consensus elements within the Bnip3 promoter suppressed the inhibitory actions of p65 and HDAC1 on Bnip3 transcription, Figure 5. Collectively, our data support the involvement of HDAC1 and p65 NF-B in repression of Bnip3 gene activation.
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=Bnip3 WT; 
=Bnip3mt.
To further prove that the inhibitory actions of HDAC1 were functionally contingent on p65 NF-B, we next tested whether HDAC1 would repress Bnip3 gene transcription in cells derived from p65–/– deficient mice. As shown in Figure 6 (panels A and B), in contrast to WT controls, basal transcription of the Bnip3 luciferase reporter as well as the endogenous Bnip3 gene were increased in p65–/– cells compared with WT cells, a finding concordant with the repression of Bnip3 by p65 NF-B and our earlier work.8 Interestingly, the ability of HDAC1 to repress Bnip3 gene transcription was lost in p65–/– cells, but was restored by repletion of the p65NF-B into p65–/– cells, Figure 6 panel A. In agreement with these findings was an increase in the endogenous basal Bnip3 gene transcription in WT p65 cells treated with TSA but not in p65–/– cells, a finding consistent with a requirement for p65 NF-B for the activity of HDAC1. Moreover, IKKß mediated NF-B activation repressed endogenous Bnip3 transcription in WT p65 cells but not in cells deficient for p65 NF-B. Importantly, the repressive effects of IKKß mediated NF-B activation on Bnip3 transcription were suppressed in WT p65 NF-B cells by TSA but not in p65–/– cells. These findings are in agreement with the dependency of HDAC1 on p65NF-B for the repression of Bnip3 gene activity, Figure 6 panel B. Taken together, the data strongly suggest that Bnip3 gene transcription is regulated by the cooperative actions of NF-B and HDAC1.
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Previously we reported that Bnip3 promoter activity was increased in ventricular myocytes during hypoxia. To ascertain whether the hypoxia-induced activation of Bnip3 is related to functional changes in HDAC1 activity, we monitored the status of HDAC activity in ventricular myocytes under normoxic and hypoxic conditions.
As shown in Figure 7, TSA inhibited HDAC activity in ventricular myocytes by 36% (P<0.05) compared with vehicle control cells. Interestingly, in contrast to normoxic cells, a significant 21% (P<0.01) reduction in HDAC activity was observed in cells subjected to hypoxia. As predicted, the combination of hypoxia plus TSA had greater repressive effect on HDAC activity than hypoxia alone. Importantly, the hypoxia-induced decrease in HDAC activity was accompanied by a concomitant 4.8-fold increase (P<0.01) in Bnip3 gene transcription, Figure 7 (panel B). Importantly, hypoxia-induced activation of Bnip3 gene was suppressed in cells expressing the WT HDAC1 but not in cells expressing the catalytically inactive HDAC1, Figure 7 (panel B). Furthermore, deletion of the NF-B elements within the Bnip3 promoter elements disrupted the inhibitory actions of HDAC 1 on Bnip3 gene transcription during hypoxia, Figure 7 (panel C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Earlier work by our laboratory established Bnip3 as a critical regulator of mitochondrial perturbations and cell death of ventricular myocytes during hypoxic injury.18 Further, we identified that the Bnip3 promoter was strongly repressed by NF-
B, however, the underlying mechanism was not determined.8 In this report, we provide new mechanistic evidence that the Bnip3 promoter is transcriptionally repressed by p65 NF-B through a mechanism that involves the recruitment and catalytic activity of HDAC1. Importantly, we show that the canonical NF-B elements within the Bnip3 promoter are crucial for transcriptional repression of Bnip3 by HDAC1.
The antithetical regulation of Bnip3 gene expression by NF-B, despite NF-B’s well established and proven role as a transcriptional activator,6,31–34 highlights a less defined but emerging role for NF-B as a transcriptional repressor.5,15,35,36 This raises the interesting possibility that NF-B may avert cell death by actively repressing certain death genes such as Bnip3. Indeed, our findings that Bnip3 gene transcription was inhibited by NF-B is consistent with this notion and in line with our earlier work demonstrating a critical role for NF-B for suppression of mitochondrial perturbations and cell death of ventricular myocytes during hypoxia.8,18
The fact that TSA alleviated the inhibitory actions of p65 NF-B on Bnip3 gene transcription is intriguing and strongly suggests the involvement of HDAC proteins in the repression of Bnip3 transcription. Interestingly, however, we noted that TSA completely abrogated the inhibitory actions of NF-B on the endogenous Bnip3 gene yet partially disrupted the effects of p65 NF-B on the Bnip3 luciferase reporter. This raises the possibility that stoichiometric differences with respect to the efficiency of HDAC inhibition by TSA may exist between the Bnip3 reporter and the endogenous Bnip3 gene. Nonetheless, our data strongly suggest the involvement of HDAC proteins in the repression of Bnip3 gene transcription by NF-B.
We focused our attention on HDAC1 for 2 important reasons: first, prior evidence for the regulation of NF-B dependent promoters by HDACs5,37 and second, perhaps most intriguing was our immunoprecipitation experiments of cardiac cell lysate which revealed interaction of p65 NF-B with HDAC1. Our findings that basal and inducible expression of Bnip3 transcription was repressed by HDAC1 verifies the operation of HDAC1 in ventricular myocytes and the notion that HDAC1 may be involved in the NF-B mediated repression of Bnip3. The interrelationship between HDAC 1 and p65 NF-B becomes even more profound given that we show by not 1 but by 3 independent approaches that functional inactivation of either factor was sufficient to derepress the Bnip3 promoter and increase Bnip3 gene transcription. For example, cells rendered defective for NF-B activation or mutations of the p65 defective for DNA binding suppressed the inhibitory actions of HDAC 1 on Bnip3 transcription. The derepression of HDAC1 on Bnip3 gene transcription by the p65 defective for DNA binding, and not by either of the transactivation defective p65 proteins highlights 2 important features of our study. First, HDAC1 activity is necessary for repression of basal and inducible Bnip3 transcription and second, that the repressive of effects of p65 NF-B on Bnip3 gene transcription is not dependent on the transactivation potential of p65NF-B. The fact that the DNA binding mutation of p65NF-B abrogated the ability of HDAC1 to repress Bnip3 transcription is consistent with a model in which p65 NF-B serves as a platform for the recruitment of HDAC1 activity. This is in-line with our data in p65–/– cells in which HDAC1 overexpression had no influence on Bnip3 gene transcription. Furthermore, deletion of the NF-B elements within the Bnip3 promoter disrupted the repressive effects of HDAC1 on basal and hypoxia-inducible Bnip3 gene activity, substantiating the importance of NF-B for repression of BNIP3 gene activity by HDAC1. Importantly, however, we cannot exclude the possibility that the NF-B signals through noncanonical or cryptic inhibitory NF-B elements nested within the Bnip3 promoter which could easily explain why deletion of the NF-B elements did not fully prevent the inhibitory actions of HDAC1.
Our finding that NF-B mediated repression of Bnip3 transcription was disrupted by the catalytically inactive HDAC1 was concordant with our TSA data and our contention that HDAC1 is involved in the p65 NF-B mediated repression of Bnip3. Together the findings of the present study suggest NF-B represses Bnip3 gene transcription through a mechanism that is mutually dependent and obligatorily linked to the catalytic activity of HDAC1. This notion is in agreement with our earlier work demonstrating increased Bnip3 transcription and cell death in ventricular myocytes rendered defective for NF-B signaling or in cells derived from p65 deficient mice.8
Given that Bnip3 gene expression would otherwise provoke mitochondrial defects and cell death, implies that Bnip3 promoter must be highly regulated and under tight transcription control.8 Indeed, Bnip3 is readily distinguished from other BH3 only members of the Bcl-2 family by at least 2 important features. First, Bnip3 expression is predominately restricted to the cardiac lineage,21,38 and second and perhaps the most compelling is the presence of NF-B consensus elements within the Bnip3 promoter that are absent from other death factors.8 This unique property of Bnip3 highlights its importance as a key regulator of the intrinsic death pathway in cardiac muscle and its transcriptional divergence from the other death factors.8 Given that earlier work from our laboratory demonstrated a direct linkage between Bcl-2 and NF-B activation for the suppression of cell death29,39,40 it is tempting to speculate that survival signals mediated by NF-B may in part involve the active transcriptional repression of certain death genes such as Bnip3 through the recruitment of HDACs. The fact that the inhibitory actions of p65 NF-B on Bnip3 transcription were suppressed by TSA or catalytically inactive HDAC1 strongly suggests the involvement and importance of the histone deacetylase activity. Whether NF-B signals through alternative inhibitory factors or is subject to posttranslational events requisite for repression of Bnip3 is currently unknown and is an area of active investigation.
Nevertheless, under the conditions tested, our data provide the first direct evidence that the death factor Bnip3 is transcriptionally repressed by the cooperative actions of NF-B and HDAC 1. Furthermore, our data provide novel insight into the cytoprotective properties conferred by NF-B that now extend to the transcriptional repression of the death gene Bnip3.
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Acknowledgments |
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We are grateful to the late Dr Arnold H. Greenberg, for his friendship and generous gift of reagents; Drs Albert Baldwin and Gioacchino Natoli for reagents cited; Drs Michael Czubryt and Harvey Weisman for critical comments on the manuscript; and Floribeth Aguilar and Alexandra Cooper for expert technical assistance.
Sources of Funding
This work was supported by grants to L.A.K from the CIHR; L.A.K. holds a Canada Research Chair in Molecular Cardiology.
Disclosures
None.
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Footnotes |
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Original received June 29, 2006; revision received October 19, 2006; accepted October 20, 2006.
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