HDAC11 suppresses the thermogenic program of adipose tissue via BRD2

Bagchi, Rushita A.; Ferguson, Bradley S.; Stratton, Matthew S.; Hu, Tianjing; Cavasin, Maria A.; Sun, Li; Lin, Ying; Liu, Dianxin; Londono, Pilar; Song, Kunhua; Pino, Maria F.; Sparks, Lauren M.; Smith, Steven R.; Scherer, Philipp E.; Collins, Sheila; Seto, Edward; McKinsey, Timothy A.

doi:10.1172/jci.insight.120159

Cited by 76 publications

(82 citation statements)

References 61 publications

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“…Adenoviral vectors were produced as described [31]. cDNA was obtained from the pET-24 vector containing a full-length rat cTnI sequence generously provided by Dr. Michael Regnier (University of Washington) [32].…”

Section: Adenoviral Productionmentioning

confidence: 99%

Site-specific acetyl-mimetic modification of cardiac troponin I modulates myofilament relaxation and calcium sensitivity

Lin

Schmidt

Fritz

et al. 2020

Journal of Molecular and Cellular Cardiology

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Cardiac troponin I (cTnI) is an essential physiological and pathological regulator of cardiac relaxation. Significant to this regulation, the post-translational modification of cTnI through phosphorylation functions as a key mechanism to accelerate myofibril relaxation. Similar to phosphorylation, post-translational modification by acetylation alters amino acid charge and protein function. Recent studies have demonstrated that the acetylation of cardiac myofibril proteins accelerates relaxation and that cTnI is acetylated in the heart. These findings highlight the potential significance of myofilament acetylation; however, it is not known if site-specific acetylation of cTnI can lead to changes in myofilament, myofibril, and/or cellular mechanics. The objective of this study was to determine the effects of mimicking acetylation at a single site of cTnI (lysine-132; K132) on myofilament, myofibril, and cellular mechanics and elucidate its influence on molecular function. Methods: To determine if pseudo-acetylation of cTnI at 132 modulates thin filament regulation of the actomyosin interaction, we reconstituted thin filaments containing WT or K132Q (to mimic acetylation) cTnI and assessed in vitro motility. To test if mimicking acetylation at K132 alters cellular relaxation, adult rat ventricular cardiomyocytes were infected with adenoviral constructs expressing either cTnI K132Q or K132 replaced with arginine (K132R; to prevent acetylation) and cell shortening and isolated myofibril mechanics were measured. Finally, to confirm that changes in cell shortening and myofibril mechanics were directly due to pseudo-acetylation of cTnI at K132, we exchanged troponin containing WT or K132Q cTnI into isolated myofibrils and measured myofibril mechanical properties. Results: Reconstituted thin filaments containing K132Q cTnI exhibited decreased calcium sensitivity compared to thin filaments reconstituted with WT cTnI. Cardiomyocytes expressing K132Q cTnI had faster relengthening and myofibrils isolated from these cells had faster relaxation along with decreased calcium sensitivity compared to cardiomyocytes expressing WT or K132R cTnI. Myofibrils exchanged with K132Q cTnI ex vivo demonstrated faster relaxation and decreased calcium sensitivity. Conclusions: Our results indicate for the first time that mimicking acetylation of a specific cTnI lysine accelerates myofilament, myofibril, and myocyte relaxation. This work underscores the importance of understanding how acetylation of specific sarcomeric proteins affects cardiac homeostasis and disease and suggests that modulation of myofilament lysine acetylation may represent a novel therapeutic target to alter cardiac relaxation.

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Section: Adenoviral Productionmentioning

confidence: 99%

Site-specific acetyl-mimetic modification of cardiac troponin I modulates myofilament relaxation and calcium sensitivity

Lin

Schmidt

Fritz

et al. 2020

Journal of Molecular and Cellular Cardiology

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“…Studies by Bagchi et al also proved that the deletion of HDAC11 inhibited the HDAC11/BRD2 association, exacerbated brown adipose tissue formation, and enhanced insulin sensitivity HDAC11-KO mice when fed with a high-fat diet. These findings suggest the function of HDAC11 in regulating whole-body metabolism and demonstrate the significance of HDAC11 inhibition for the treatment of diabetes and its complications [ 61 ]. In the present investigation, we observed a significant increase in HDAC11 among T2DM and DFU patients.…”

Section: Discussionmentioning

confidence: 95%

Gene Expression Profiling of Multiple Histone Deacetylases (HDAC) and Its Correlation with NRF2-Mediated Redox Regulation in the Pathogenesis of Diabetic Foot Ulcers

et al. 2020

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Nuclear factor erythroid-2-related factor 2 (Nrf2) is a protein of the leucine zipper family, which mitigates inflammation and employs cytoprotective effects. Attempting to unravel the epigenetic regulation of type 2 diabetes mellitus (T2DM) and diabetic foot ulcer (DFU), we profiled the expression of eleven isoform-specific histone deacetylases (HDACs) and correlated them with NRF2 and cytokines. This study recruited a total of 60 subjects and categorized into DFU patients (n = 20), T2DM patients (n = 20), and healthy controls (n = 20). The DFU patients were subcategorized into uninfected and infected DFU (n = 10 each). We observed a progressive decline in the expression of NRF2 and its downstream targets among T2DM and DFU subjects. The inflammatory markers IL-6 and TNF-α were significantly upregulated, whereas anti-inflammatory marker IL-10 was significantly downregulated in DFU. Of note, a significant upregulation of HDAC1, 3, 4, 11, SIRT3 and downregulation of HDAC2,8, SIRT1, SIRT2, SIRT3, SIRT7 among DFU patients were observed. The significant positive correlation between NRF2 and SIRT1 in DFU patients suggested the vital role of NRF2/SIRT1 in redox homeostasis and angiogenesis. In contrast, the significant negative correlation between NRF2 and HDAC1, 3 and 4, implied an imbalance in NRF2-HDAC1, 3, 4 circuit. Furthermore, a significant positive correlation was observed between HDAC4 and IL-6, and the negative correlation between SIRT1 and IL-6 suggested the pro-inflammatory role of HDAC4 and the anti-inflammatory role of SIRT1 in NRF2 signaling. In conclusion, the epigenetic changes such as upregulation of HDAC1, 3, 4, 11, SIRT3 and downregulation of HDAC2, 8, SIRT1, SIRT2, SIRT6, SIRT7 and their association with NRF2 as well as inflammatory markers are suggestive of their roles in pathophysiology of T2DM and DFU.

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“…Therefore, it remains uncertain whether the anti-fibrotic effects of quisinostat administration are achieved by HDAC11 inhibition. Future studies employing tissue-specific HDAC11 knockout mice (Bagchi et al, 2018) will hopefully provide solid genetic evidence to ascertain the role of HDAC11 in renal fibrosis. Second, the in vitro data were based on a single cell model (Ang II treated human tubular epithelial cells), which makes it difficult to reconcile them with the in vivo data especially in the light of the recent finding that tubular epithelial cells derived myofibroblasts only constitute a small fraction of the overall population of myofibroblasts in the fibrotic kidneys in mice (LeBleu et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase 11 Contributes to Renal Fibrosis by Repressing KLF15 Transcription

Mao

Liu

Zhang

et al. 2020

Front. Cell Dev. Biol.

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Renal fibrosis represents a key pathophysiological process in patients with chronic kidney diseases (CKD) and is typically associated with a poor prognosis. Renal tubular epithelial cells (RTECs), in response to a host of pro-fibrogenic stimuli, can trans-differentiate into myofibroblast-like cells and produce extracellular matrix proteins to promote renal fibrosis. In the present study we investigated the role of histone deacetylase 11 (HDAC11) in this process and the underlying mechanism. We report that expression levels of HDAC11 were up-regulated in the kidneys in several different animal models of renal fibrosis. HDAC11 was also up-regulated by treatment of Angiotensin II (Ang II) in cultured RTECs. Consistently, pharmaceutical inhibition with a smallmolecule inhibitor of HDAC11 (quisinostat) attenuated unilateral ureteral obstruction (UUO) induced renal fibrosis in mice. Similarly, HDAC11 inhibition by quisinostat or HDAC11 depletion by siRNA blocked Ang II induced pro-fibrogenic response in cultured RTECs. Mechanistically, HDAC11 interacted with activator protein 2 (AP-2α) to repress the transcription of Kruppel-like factor 15 (KLF15). In accordance, KLF15 knockdown antagonized the effect of HDAC11 inhibition or depletion and enabled Ang II to promote fibrogenesis in RTECs. Therefore, we data unveil a novel AP-2α-HDAC11-KLF15 axis that contributes to renal fibrosis.

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HDAC11 suppresses the thermogenic program of adipose tissue via BRD2

Cited by 76 publications

References 61 publications

Site-specific acetyl-mimetic modification of cardiac troponin I modulates myofilament relaxation and calcium sensitivity

Site-specific acetyl-mimetic modification of cardiac troponin I modulates myofilament relaxation and calcium sensitivity

Gene Expression Profiling of Multiple Histone Deacetylases (HDAC) and Its Correlation with NRF2-Mediated Redox Regulation in the Pathogenesis of Diabetic Foot Ulcers

Histone Deacetylase 11 Contributes to Renal Fibrosis by Repressing KLF15 Transcription

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