The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Mukesh K. Jain - One of the best experts on this subject based on the ideXlab platform.
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adipose KLF15 controls lipid handling to adapt to nutrient availability
Cell Reports, 2017Co-Authors: Rongli Zhang, Keiichiro Matoba, Domenick A Prosdocimo, Panjamaporn Sangwung, Eric Chen, Benlian Wang, Mukesh K. JainAbstract:Adipose tissue stores energy in the form of triglycerides. The ability to regulate triglyceride synthesis and breakdown based on nutrient status (e.g., fed versus fasted) is critical for physiological homeostasis and dysregulation of this process can contribute to metabolic disease. Whereas much is known about hormonal control of this cycle, transcriptional regulation is not well understood. Here, we show that the transcription factor Kruppel-like factor 15 (KLF15) is critical for the control of adipocyte lipid turnover. Mice lacking KLF15 in adipose tissue (AK15KO) display decreased adiposity and are protected from diet-induced obesity. Mechanistic studies suggest that adipose KLF15 regulates key genes of triglyceride synthesis and inhibits lipolytic action, thereby promoting lipid storage in an insulin-dependent manner. Finally, AK15KO mice demonstrate accelerated lipolysis and altered systemic energetics (e.g., locomotion, ketogenesis) during fasting conditions. Our study identifies adipose KLF15 as an essential regulator of adipocyte lipid metabolism and systemic energy balance.
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KLF15 establishes the landscape of diurnal expression in the heart
Cell Reports, 2015Co-Authors: Lilei Zhang, Rongli Zhang, Domenick A Prosdocimo, Xudong Liao, Xiaodong Bai, Frank E Campbell, Jeff Coller, Mukesh K. JainAbstract:Circadian rhythms offer temporal control of anticipatory physiologic adaptations in animals. In the mammalian cardiovascular system, the importance of these rhythms is underscored by increased cardiovascular disease in shift workers, findings recapitulated in experimental animal models. However, a nodal regulator that allows integration of central and peripheral information and coordinates cardiac rhythmic output has been elusive. Here, we show that kruppel-like factor 15 (KLF15) governs a biphasic transcriptomic oscillation in the heart with a maximum ATP production phase and a remodeling and repair phase corresponding to the active and resting phase of a rodent. Depletion of KLF15 in cardiomyocytes leads to a disorganized oscillatory behavior without phasic partition despite an intact core clock. Thus, KLF15 is a nodal connection between the clock and meaningful rhythmicity in the heart.
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response element composition governs correlations between binding site affinity and transcription in glucocorticoid receptor feed forward loops
Journal of Biological Chemistry, 2015Co-Authors: Sarah K. Sasse, Mukesh K. Jain, Vineela Kadiyala, Tzu Phang, Zheng Zuo, Liyang Zhang, Miles A Pufall, Gary D Stormo, Anthony N. GerberAbstract:Combinatorial gene regulation through feed-forward loops (FFLs) can bestow specificity and temporal control to client gene expression; however, characteristics of binding sites that mediate these effects are not established. We previously showed that the glucocorticoid receptor (GR) and KLF15 form coherent FFLs that cooperatively induce targets such as the amino acid-metabolizing enzymes AASS and PRODH and incoherent FFLs exemplified by repression of MT2A by KLF15. Here, we demonstrate that GR and KLF15 physically interact and identify low affinity GR binding sites within glucocorticoid response elements (GREs) for PRODH and AASS that contribute to combinatorial regulation with KLF15. We used deep sequencing and electrophoretic mobility shift assays to derive in vitro GR binding affinities across sequence space. We applied these data to show that AASS GRE activity correlated (r(2) = 0.73) with predicted GR binding affinities across a 50-fold affinity range in transfection assays; however, the slope of the linear relationship more than doubled when KLF15 was expressed. Whereas activity of the MT2A GRE was even more strongly (r(2) = 0.89) correlated with GR binding site affinity, the slope of the linear relationship was sharply reduced by KLF15, consistent with incoherent FFL logic. Thus, GRE architecture and co-regulator expression together determine the functional parameters that relate GR binding site affinity to hormone-induced transcriptional responses. Utilization of specific affinity response functions and GR binding sites by FFLs may contribute to the diversity of gene expression patterns within GR-regulated transcriptomes.
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megamitochondria in cardiomyocytes of a knockout KLF15 mouse
Ultrastructural Pathology, 2015Co-Authors: Bernard Tandler, Charles L. Hoppel, Hisashi Fujioka, Saptarsi M. Haldar, Mukesh K. JainAbstract:AbstractThe Kruppel-like factors (KLF) family of zinc-finger transcriptional regulators control many aspects of cardiomyocyte structure and function. Deletion of KLF15 from the nuclear genome in mice affects cardiac mitochondria. Some become grossly enlarged, extending many sarcomeres in length. These display many sites of incipient pinching, but there is little attenuation of the megamitochondria at these sites; there are no examples of organelles that clearly have reached the point where further membrane encroachment will cause separation into smaller daughter mitochondria. It is clear that deletion of KLF15 interferes with nuclear control of mitochondrial fission, whereas fusion appears to be unaffected.
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KLF15 and pparα cooperate to regulate cardiomyocyte lipid gene expression and oxidation
Ppar Research, 2015Co-Authors: Domenick A Prosdocimo, Rongli Zhang, Lilei Zhang, Jenine E John, Elizabeth S Efraim, Xudong Liao, Mukesh K. JainAbstract:The metabolic myocardium is an omnivore and utilizes various carbon substrates to meet its energetic demand. While the adult heart preferentially consumes fatty acids (FAs) over carbohydrates, myocardial fuel plasticity is essential for organismal survival. This metabolic plasticity governing fuel utilization is under robust transcriptional control and studies over the past decade have illuminated members of the nuclear receptor family of factors (e.g., PPARα) as important regulators of myocardial lipid metabolism. However, given the complexity of myocardial metabolism in health and disease, it is likely that other molecular pathways are likely operative and elucidation of such pathways may provide the foundation for novel therapeutic approaches. We previously demonstrated that Kruppel-like factor 15 (KLF15) is an independent regulator of cardiac lipid metabolism thus raising the possibility that KLF15 and PPARα operate in a coordinated fashion to regulate myocardial gene expression requisite for lipid oxidation. In the current study, we show that KLF15 binds to, cooperates with, and is required for the induction of canonical PPARα-mediated gene expression and lipid oxidation in cardiomyocytes. As such, this study establishes a molecular module involving KLF15 and PPARα and provides fundamental insights into the molecular regulation of cardiac lipid metabolism.
Saptarsi M. Haldar - One of the best experts on this subject based on the ideXlab platform.
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megamitochondria in cardiomyocytes of a knockout KLF15 mouse
Ultrastructural Pathology, 2015Co-Authors: Bernard Tandler, Charles L. Hoppel, Hisashi Fujioka, Saptarsi M. Haldar, Mukesh K. JainAbstract:AbstractThe Kruppel-like factors (KLF) family of zinc-finger transcriptional regulators control many aspects of cardiomyocyte structure and function. Deletion of KLF15 from the nuclear genome in mice affects cardiac mitochondria. Some become grossly enlarged, extending many sarcomeres in length. These display many sites of incipient pinching, but there is little attenuation of the megamitochondria at these sites; there are no examples of organelles that clearly have reached the point where further membrane encroachment will cause separation into smaller daughter mitochondria. It is clear that deletion of KLF15 interferes with nuclear control of mitochondrial fission, whereas fusion appears to be unaffected.
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the glucocorticoid receptor and KLF15 regulate gene expression dynamics and integrate signals through feed forward circuitry
Molecular and Cellular Biology, 2013Co-Authors: Sarah K. Sasse, Saptarsi M. Haldar, Mukesh K. Jain, Christina M Mailloux, Andrea J Barczak, Qian Wang, Mohammed O Altonsy, Anthony N. GerberAbstract:The glucocorticoid receptor (GR) regulates adaptive transcriptional programs that alter metabolism in response to stress. Network properties that allow GR to tune gene expression to match specific physiologic demands are poorly understood. We analyzed the transcriptional consequences of GR activation in murine lungs deficient for KLF15, a transcriptional regulator of amino acid metabolism that is induced by glucocorticoids and fasting. Approximately 7% of glucocorticoid-regulated genes had altered expression in KLF15-knockdown (KLF15−/−) mice. KLF15 formed coherent and incoherent feed-forward circuits with GR that correlated with the expression dynamics of the glucocorticoid response. Coherent feed-forward gene regulation by GR and KLF15 was characterized by combinatorial activation of linked GR-KLF15 regulatory elements by both factors and increased GR occupancy, while expression of KLF15 reduced GR occupancy at the incoherent target, MT2A. Serum deprivation, which increased KLF15 expression in a GR-independent manner in vitro, enhanced glucocorticoid-mediated induction of feed-forward targets of GR and KLF15, such as the loci for the amino acid-metabolizing enzymes proline dehydrogenase and alpha-aminoadipic semialdehyde synthase. Our results establish feed-forward architecture as an organizational principle for the GR network and provide a novel mechanism through which GR integrates signals and regulates expression dynamics.
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circadian rhythms govern cardiac repolarization and arrhythmogenesis
Nature, 2012Co-Authors: Darwin Jeyaraj, Yuan Lu, Saptarsi M. Haldar, Mark D Mccauley, Juergen Ripperger, Kun Hu, Betty L Eapen, Nikunj Sharma, Eckhard Ficker, Michael J CutlerAbstract:Circadian rhythmicity of cardiac ion-channel expression and of an index of myocardial repolarization is under the control of KLF15, a clock-dependent oscillator that is required for generating transient outward potassium current, and deficiencies or excesses of which cause loss of rhythmic variation in myocardial and abnormal repolarization, and an enhanced susceptibility to ventricular arrhythmias. Several physiological parameters in the cardiovascular system show diurnal variation. Mukesh Jain and colleagues now provide a link between circadian rhythms and arrhythmogenesis in mice. They show that the transcription factor KLF15 is regulated by components of the circadian clock, and KLF15 in turn regulates expression of the ion channel KChIP2. In gain- and loss-of-function experiments, the authors show that KLF15 regulates temporal variation in cardiac repolarization and susceptibility to arrhythmias. The findings raise the possibility that circadian factors contribute to the diurnal variation seen in occurrence of sudden cardiac death. Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease1,2, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure)3,4,5 or pattern (for example, Brugada’s syndrome)6 of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, kruppel-like factor 15 (KLF15). KLF15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current7. Deficiency or excess of KLF15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac arrhythmogenesis.
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circadian rhythms govern cardiac repolarization and arrhythmogenesis
Nature, 2012Co-Authors: Darwin Jeyaraj, Saptarsi M. Haldar, Mark D Mccauley, Juergen Ripperger, Betty L Eapen, Nikunj Sharma, Eckhard Ficker, Michael J Cutler, Xiaoping Wan, James GulickAbstract:Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure) or pattern (for example, Brugada's syndrome) of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, kruppel-like factor 15 (KLF15). KLF15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current. Deficiency or excess of KLF15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac arrhythmogenesis.
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expression profiling identifies KLF15 as a glucocorticoid target that regulates airway hyperresponsiveness
American Journal of Respiratory Cell and Molecular Biology, 2011Co-Authors: Kiriko Masuno, Saptarsi M. Haldar, Mukesh K. Jain, Christina M Mailloux, Darwin Jeyaraj, Xiaozhu Huang, Rey A Panettieri, Anthony N. GerberAbstract:Glucocorticoids (GCs), which activate GC receptor (GR) signaling and thus modulate gene expression, are widely used to treat asthma. GCs exert their therapeutic effects in part through modulating airway smooth muscle (ASM) structure and function. However, the effects of genes that are regulated by GCs on airway function are not fully understood. We therefore used transcription profiling to study the effects of a potent GC, dexamethasone, on human ASM (HASM) gene expression at 4 and 24 hours. After 24 hours of dexamethasone treatment, nearly 7,500 genes had statistically distinguishable changes in expression; quantitative PCR validation of a 40-gene subset of putative GR-regulated genes in 6 HASM cell lines suggested that the early transcriptional targets of GR signaling are similar in independent HASM lines. Gene ontology analysis implicated GR targets in controlling multiple aspects of ASM function. One GR-regulated gene, the transcription factor, Kruppel-like factor 15 (KLF15), was already known to modulate vascular smooth and cardiac muscle function, but had no known role in the lung. We therefore analyzed the pulmonary phenotype of KLF15(-/-) mice after ovalbumin sensitization and challenge. We found diminished airway responses to acetylcholine in ovalbumin-challenged KLF15(-/-) mice without a significant change in the induction of asthmatic inflammation. In cultured cells, overexpression of KLF15 reduced proliferation of HASM cells, whereas apoptosis in KLF15(-/-) murine ASM cells was increased. Together, these results further characterize the GR-regulated gene network in ASM and establish a novel role for the GR target, KLF15, in modulating airway function.
Susan Gray - One of the best experts on this subject based on the ideXlab platform.
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low protein diet supplemented with ketoacids reduces the severity of renal disease in 5 6 nephrectomized rats a role for KLF15
Kidney International, 2011Co-Authors: Xiang Gao, Susan Gray, Mukesh K. Jain, Lianghu Huang, Fabrizio Grosjean, Vittoria Esposito, Jiangming Tan, Feng Zheng, Changlin MeiAbstract:Dietary protein restriction is an important treatment for chronic kidney disease. Herein, we tested the effect of low-protein or low-protein plus ketoacids (KA) diet in a remnant kidney model. Rats with a remnant kidney were randomized to receive normal protein diet (22%), low-protein (6%) diet (LPD), or low-protein (5%) plus KA (1%) diet for 6 months. Protein restriction prevented proteinuria, decreased blood urea nitrogen levels, and renal lesions; however, the LPD retarded growth and decreased serum albumin levels. Supplementation with KA corrected these abnormalities and provided superior renal protection compared with protein restriction alone. The levels of Kruppel-like factor-15 (KLF15), a transcription factor shown to reduce cardiac fibrosis, were decreased in remnant kidneys. Protein restriction, which increased KLF15 levels in the normal kidney, partially recovered the levels of KLF15 in remnant kidney. The expression of KLF15 in mesangial cells was repressed by oxidative stress, transforming growth factor-β, and tumor necrosis factor (TNF)-α. The suppressive effect of TNF-α on KLF15 expression was mediated by TNF receptor-1 and nuclear factor-κB. Overexpression of KLF15 in mesangial and HEK293 cells significantly decreased fibronectin and type IV collagen mRNA levels. Furthermore, KLF15 knockout mice developed glomerulosclerosis following uninephrectomy. Thus, KLF15 may be an antifibrotic factor in the kidney, and its decreased expression may contribute to the progression of kidney disease.
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the kruppel like factor KLF15 inhibits connective tissue growth factor ctgf expression in cardiac fibroblasts
Journal of Molecular and Cellular Cardiology, 2008Co-Authors: Baiqiu Wang, Osama A Ibrahim, Sudeshna Fisch, Andrew Leask, Susan Gray, Yuan Lu, Saptarsi M. Haldar, Mukesh K. JainAbstract:Cardiac fibrosis is a hallmark feature of pathologic remodeling of the heart in response to hemodynamic or neurohormonal stress. Accumulating evidence implicates connective tissue growth factor (CTGF) as a key mediator of this process. Our group has previously identified Kruppel-Like Factor 15 (KLF15) as an important regulator of cardiac remodeling in response to stress; however, the role of this transcription factor in cardiac fibrosis has not been reported. Here we provide evidence that treatment of neonatal rat ventricular fibroblasts (NRVFs) with the potent pro-fibrotic agent Transforming Growth Factor-β1 (TGFβ1) strongly reduces KLF15 expression while inducing the pro-fibrotic factor CTGF. Adenoviral overexpression of KLF15 inhibits basal and TGFβ1-induced CTGF expression in NRVFs. Furthermore, hearts from KLF15 −/− mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. From a mechanistic standpoint, KLF15 inhibits basal and TGFβ1-mediated induction of the CTGF promoter. Chromatin Immunoprecipitation (ChIP) and electrophoretic mobility shift assays demonstrate that KLF15 inhibits recruitment of the coactivator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. Consistent with this observation, KLF15 mediated repression of the CTGF promoter is rescued by P/CAF overexpression. Our result implicates KLF15 as a novel negative regulator of CTGF expression and cardiac fibrosis.
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the kruppel like factor KLF15 inhibits connective tissue growth factor ctgf expression in cardiac fibroblasts
Journal of Molecular and Cellular Cardiology, 2008Co-Authors: Baiqiu Wang, Osama A Ibrahim, Sudeshna Fisch, Andrew Leask, Susan Gray, Saptarsi M. Haldar, Mukesh K. JainAbstract:Cardiac fibrosis is a hallmark feature of pathologic remodeling of the heart in response to hemodynamic or neurohormonal stress. Accumulating evidence implicates connective tissue growth factor (CTGF) as a key mediator of this process. Our group has previously identified Kruppel-Like Factor 15 (KLF15) as an important regulator of cardiac remodeling in response to stress; however, the role of this transcription factor in cardiac fibrosis has not been reported. Here we provide evidence that treatment of neonatal rat ventricular fibroblasts (NRVFs) with the potent pro-fibrotic agent Transforming Growth Factor-beta1 (TGFbeta1) strongly reduces KLF15 expression while inducing the pro-fibrotic factor CTGF. Adenoviral overexpression of KLF15 inhibits basal and TGFbeta1-induced CTGF expression in NRVFs. Furthermore, hearts from KLF15-/- mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. From a mechanistic standpoint, KLF15 inhibits basal and TGFbeta1-mediated induction of the CTGF promoter. Chromatin Immunoprecipitation (ChIP) and electrophoretic mobility shift assays demonstrate that KLF15 inhibits recruitment of the co-activator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. Consistent with this observation, KLF15 mediated repression of the CTGF promoter is rescued by P/CAF overexpression. Our result implicates KLF15 as a novel negative regulator of CTGF expression and cardiac fibrosis.
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regulation of gluconeogenesis by kruppel like factor 15
Cell Metabolism, 2007Co-Authors: Susan Gray, Sudeshna Fisch, Baiqiu Wang, Saptarsi M. Haldar, Yvette Orihuela, Eun Gyoung Hong, Gary W Cline, Odile D Peroni, Barbara B KahnAbstract:Summary In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy. After an overnight fast, hepatic glycogen stores are depleted, and gluconeogenesis becomes essential for preventing life-threatening hypoglycemia. Mice with a targeted deletion of KLF15 , a member of the Kruppel-like family of transcription factors, display severe hypoglycemia after an overnight (18 hr) fast. We provide evidence that defective amino acid catabolism promotes the development of fasting hypoglycemia in KLF15 −/− mice by limiting gluconeogenic substrate availability. KLF15 −/− liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes. Furthermore, the enzymatic activity of alanine aminotransferase (ALT), which converts the critical gluconeogenic amino acid alanine into pyruvate, is decreased (∼50%) in KLF15 −/− hepatocytes. Consistent with this observation, intraperitoneal injection of pyruvate, but not alanine, rescues fasting hypoglycemia in KLF15 −/− mice. We conclude that KLF15 plays an important role in the regulation of gluconeogenesis.
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the kruppel like factor KLF15 regulates the insulin sensitive glucose transporter glut4
Journal of Biological Chemistry, 2002Co-Authors: Susan Gray, Mark W Feinberg, Sarah C Hull, Chay T Kuo, Masafumi Watanabe, Sucharita Sen Banerjee, Ana S Depina, Richard L Haspel, Mukesh K. JainAbstract:Resistance to the stimulatory effects of insulin on glucose utilization is a key feature of type 2 diabetes, obesity, and the metabolic syndrome. Recent studies suggest that insulin resistance is primarily caused by a defect in glucose transport. GLUT4 is the main insulin-responsive glucose transporter and is expressed predominantly in muscle and adipose tissues. Whereas GLUT4 has been shown to play a critical role in maintaining systemic glucose homeostasis, the mechanisms regulating its expression are incompletely understood. We have cloned the murine homologue of KLF15, a member of the Kru¨ppel-like family of transcription factors. KLF15 is highly expressed in adipocytes and myocytes in vivo and is induced when 3T3-L1 preadipocytes are differentiated into adipocytes. Overexpression of KLF15 in adipose and muscle cell lines potently induces GLUT4 expression. This effect is specific to KLF15 as overexpression of two other Kru¨ppel-like factors, KLF2/LKLF and KLF4/GKLF, did not induce GLUT4 expression. Both basal (3.3-fold, p
Deborah C Otteson - One of the best experts on this subject based on the ideXlab platform.
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novel roles and mechanism for kruppel like factor 16 klf16 regulation of neurite outgrowth and ephrin receptor a5 epha5 expression in retinal ganglion cells
Journal of Biological Chemistry, 2016Co-Authors: Jianbo Wang, Joana Galvao, Krista M Beach, Raul Urrutia, Jeffrey L Goldberg, Deborah C OttesonAbstract:Abstract Regenerative medicine holds great promise for the treatment of degenerative retinal disorders. Kruppel-like factors (KLFs) are transcription factors that have recently emerged as key tools in regenerative medicine because some of them can function as epigenetic reprogrammers in stem cell biology. Here, we show that KLF16, one of the least understood members of this family, is a POU4F2 independent transcription factor in retinal ganglion cells (RGCs) as early as embryonic day 15. When overexpressed, KLF16 inhibits RGC neurite outgrowth and enhances RGC growth cone collapse in response to exogenous ephrinA5 ligands. Ephrin/EPH signaling regulates RGC connectivity. The EphA5 promoter contains multiple GC- and GT-rich KLF-binding sites, which, as shown by ChIP-assays, bind KLF16 in vivo. In electrophoretic mobility shift assays, KLF16 binds specifically to a single KLF site near the EphA5 transcription start site that is required for KLF16 transactivation. Interestingly, methylation of only six of 98 CpG dinucleotides within the EphA5 promoter blocks its transactivation by KLF16 but enables transactivation by KLF2 and KLF15. These data demonstrate a role for KLF16 in regulation of RGC neurite outgrowth and as a methylation-sensitive transcriptional regulator of EphA5 expression. Together, these data identify differential low level methylation as a novel mechanism for regulating KLF16-mediated EphA5 expression across the retina. Because of the critical role of ephrin/EPH signaling in patterning RGC connectivity, understanding the role of KLFs in regulating neurite outgrowth and Eph receptor expression will be vital for successful restoration of functional vision through optic nerve regenerative therapies.
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zinc finger domains of the transcriptional repressor KLF15 bind multiple sites in rhodopsin and irbp promoters including the crs 1 and g rich repressor elements
BMC Molecular Biology, 2005Co-Authors: Deborah C Otteson, Hong Lai, Yuhui Liu, Donald J ZackAbstract:In the retina, many of the genes that encode components of the visual transduction cascade and retinoid recycling are exclusively expressed in photoreceptor cells and show highly stereotyped temporal and spatial expression patterns. Multiple transcriptional activators of photoreceptor-specific genes have been identified, but little is known about negative regulation of gene expression in the retina. We recently identified KLF15, a member of the Sp/Kruppel-like Factor family of zinc-finger containing transcription factors, as an in vitro repressor of the promoters of the photoreceptor-specific genes rhodopsin and IRBP/Rbp3. To gain further insight into the mechanism of KLF15-mediated regulation of gene expression, we have characterized the binding characteristics and specificity of KLF15's DNA binding domains and defined the KLF15 binding sites in the rhodopsin and IRBP promoters. In EMSA and DNAseI footprinting assays, a KLF15-GST fusion protein containing the C-terminal zinc-finger domains (123 amino acids) showed zinc-dependent and sequence-specific binding to a 9 bp consensus sequence containing a core CG/TCCCC. Both the bovine rhodopsin and IRBP promoters contained multiple KLF15 binding sites that included the previously identified CRS-1 and G-rich repressor elements. KLF15 binding sites were highly conserved between the bovine, human, chimp and dog rhodopsin promoters, but less conserved in rodents. KLF15 reduced luciferase expression by bRho130-luc (containing 4 KLF15 sites) and repressed promoter activation by CRX (cone rod homeobox) and/or NRL (neural retina leucine zipper), although the magnitude of the reduction was smaller than previously reported for a longer bRho225-luc (containing 6 KFL15 sites). KLF15 binds to multiple 9 bp consensus sites in the Rhodospin and IRBP promoters including the CRS-1 and G-rich repressor elements. Based on the known expression pattern of KLF15 in non-photoreceptor cells, we hypothesize an in vivo role for KLF15 in repressing photoreceptor-specific gene expression in the inner retina.
Baiqiu Wang - One of the best experts on this subject based on the ideXlab platform.
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the kruppel like factor KLF15 inhibits connective tissue growth factor ctgf expression in cardiac fibroblasts
Journal of Molecular and Cellular Cardiology, 2008Co-Authors: Baiqiu Wang, Osama A Ibrahim, Sudeshna Fisch, Andrew Leask, Susan Gray, Yuan Lu, Saptarsi M. Haldar, Mukesh K. JainAbstract:Cardiac fibrosis is a hallmark feature of pathologic remodeling of the heart in response to hemodynamic or neurohormonal stress. Accumulating evidence implicates connective tissue growth factor (CTGF) as a key mediator of this process. Our group has previously identified Kruppel-Like Factor 15 (KLF15) as an important regulator of cardiac remodeling in response to stress; however, the role of this transcription factor in cardiac fibrosis has not been reported. Here we provide evidence that treatment of neonatal rat ventricular fibroblasts (NRVFs) with the potent pro-fibrotic agent Transforming Growth Factor-β1 (TGFβ1) strongly reduces KLF15 expression while inducing the pro-fibrotic factor CTGF. Adenoviral overexpression of KLF15 inhibits basal and TGFβ1-induced CTGF expression in NRVFs. Furthermore, hearts from KLF15 −/− mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. From a mechanistic standpoint, KLF15 inhibits basal and TGFβ1-mediated induction of the CTGF promoter. Chromatin Immunoprecipitation (ChIP) and electrophoretic mobility shift assays demonstrate that KLF15 inhibits recruitment of the coactivator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. Consistent with this observation, KLF15 mediated repression of the CTGF promoter is rescued by P/CAF overexpression. Our result implicates KLF15 as a novel negative regulator of CTGF expression and cardiac fibrosis.
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the kruppel like factor KLF15 inhibits connective tissue growth factor ctgf expression in cardiac fibroblasts
Journal of Molecular and Cellular Cardiology, 2008Co-Authors: Baiqiu Wang, Osama A Ibrahim, Sudeshna Fisch, Andrew Leask, Susan Gray, Saptarsi M. Haldar, Mukesh K. JainAbstract:Cardiac fibrosis is a hallmark feature of pathologic remodeling of the heart in response to hemodynamic or neurohormonal stress. Accumulating evidence implicates connective tissue growth factor (CTGF) as a key mediator of this process. Our group has previously identified Kruppel-Like Factor 15 (KLF15) as an important regulator of cardiac remodeling in response to stress; however, the role of this transcription factor in cardiac fibrosis has not been reported. Here we provide evidence that treatment of neonatal rat ventricular fibroblasts (NRVFs) with the potent pro-fibrotic agent Transforming Growth Factor-beta1 (TGFbeta1) strongly reduces KLF15 expression while inducing the pro-fibrotic factor CTGF. Adenoviral overexpression of KLF15 inhibits basal and TGFbeta1-induced CTGF expression in NRVFs. Furthermore, hearts from KLF15-/- mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. From a mechanistic standpoint, KLF15 inhibits basal and TGFbeta1-mediated induction of the CTGF promoter. Chromatin Immunoprecipitation (ChIP) and electrophoretic mobility shift assays demonstrate that KLF15 inhibits recruitment of the co-activator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. Consistent with this observation, KLF15 mediated repression of the CTGF promoter is rescued by P/CAF overexpression. Our result implicates KLF15 as a novel negative regulator of CTGF expression and cardiac fibrosis.
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kruppel like factor 15 is a regulator of cardiomyocyte hypertrophy
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Sudeshna Fisch, Baiqiu Wang, Saptarsi M. Haldar, Stephane Heymans, Otmar Pfister, Lei Cui, Ajay Kumar, Zhiyong Lin, Susan H Gray, Sucharita SenbanerjeeAbstract:Cardiac hypertrophy is a common response to injury and hemodynamic stress and an important harbinger of heart failure and death. Herein, we identify the Kruppel-like factor 15 (KLF15) as an inhibitor of cardiac hypertrophy. Myocardial expression of KLF15 is reduced in rodent models of hypertrophy and in biopsy samples from patients with pressure-overload induced by chronic valvular aortic stenosis. Overexpression of KLF15 in neonatal rat ventricular cardiomyocytes inhibits cell size, protein synthesis and hypertrophic gene expression. KLF15-null mice are viable but, in response to pressure overload, develop an eccentric form of cardiac hypertrophy characterized by increased heart weight, exaggerated expression of hypertrophic genes, left ventricular cavity dilatation with increased myocyte size, and reduced left ventricular systolic function. Mechanistically, a combination of promoter analyses and gel-shift studies suggest that KLF15 can inhibit GATA4 and myocyte enhancer factor 2 function. These studies identify KLF15 as part of a heretofore unrecognized pathway regulating the cardiac response to hemodynamic stress.
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regulation of gluconeogenesis by kruppel like factor 15
Cell Metabolism, 2007Co-Authors: Susan Gray, Sudeshna Fisch, Baiqiu Wang, Saptarsi M. Haldar, Yvette Orihuela, Eun Gyoung Hong, Gary W Cline, Odile D Peroni, Barbara B KahnAbstract:Summary In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy. After an overnight fast, hepatic glycogen stores are depleted, and gluconeogenesis becomes essential for preventing life-threatening hypoglycemia. Mice with a targeted deletion of KLF15 , a member of the Kruppel-like family of transcription factors, display severe hypoglycemia after an overnight (18 hr) fast. We provide evidence that defective amino acid catabolism promotes the development of fasting hypoglycemia in KLF15 −/− mice by limiting gluconeogenic substrate availability. KLF15 −/− liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes. Furthermore, the enzymatic activity of alanine aminotransferase (ALT), which converts the critical gluconeogenic amino acid alanine into pyruvate, is decreased (∼50%) in KLF15 −/− hepatocytes. Consistent with this observation, intraperitoneal injection of pyruvate, but not alanine, rescues fasting hypoglycemia in KLF15 −/− mice. We conclude that KLF15 plays an important role in the regulation of gluconeogenesis.