Gene expression profiles from the cardiac tissue of HIPK2-knockout and Wild Type (WT) mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE169429 | GEO | 2022/01/01
REPOSITORIES: GEO
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Project description:Background: Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we employed an integrated transcriptomics and bioinformatics analysis and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. The role of HIPK2 in cardiac biology is unknown. Methods: We used the Expression2Kinase algorithm for the screening of kinase targets. To determine the role of HIPK2 in the heart, we generated cardiomyocyte-specific HIPK2 knockout (CM-KO) and heterozygous (CM-Het) mice. Heart function was examined by echocardiography and related cellular and molecular mechanisms were examined. Adeno-associated virus serotype 9 (AAV9) carrying cardiac-specific constitutively active MEK1 (TnT-MEK1-CA) were administrated to rescue cardiac dysfunction in CM-KOs. Results: To our knowledge, this is the first study to define the role of HIPK2 in cardiac biology. Using multiple HIPK2 loss-of-function mouse models, we demonstrated that reduction of HIPK2 in cardiomyocytes leads to cardiac dysfunction—suggesting a causal role in heart failure. Importantly, cardiac dysfunction in HIPK2 KOs developed with advancing age, but not during development. In addition, CM-KO and CM-Het exhibited a gene dose-response relationship of cardiomyocyte HIPK2 on heart function. HIPK2 expression in the heart was significantly reduced in human end-stage ischemic cardiomyopathy compared to non-failing myocardium, suggesting a clinical relevance of HIPK2 in cardiac biology. In vitro studies with neonatal rat ventricular cardiomyocytes corroborated the in vivo findings. Specifically, adenovirus-mediated overexpression of HIPK2 suppressed the expression of heart failure markers, NPPA and NPPB, at basal condition and abolished phenylephrine-induced pathological gene expression. An array of mechanistic studies revealed impaired ERK1/2 signaling in HIPK2 deficient hearts. In vivo rescue experiment with AAV9 TnT-MEK1-CA nearly abolished the detrimental phenotype of KOs suggesting that impaired ERK signaling mediated apoptosis as the key factor driving the detrimental phenotype in CM-KO hearts. Conclusions: Taken together, these findings suggest that cardiomyocyte HIPK2 is required to maintain normal cardiac function via ERK signaling
2019-08-27 | GSE136308 | GEO
Project description:Gene expression profiles from the cardiac tissue of HIPK2-knockout and Wild Type (WT) mice
| PRJNA716600 | ENA
Project description:The androgen receptor (AR) is a mediator of both androgen-dependent and castration- resistant prostate cancers. Identification of cellular factors affecting AR transcriptional activity could in principle yield new targets that reduce AR activity and combat prostate cancer, yet a comprehensive analysis of the genes required for AR-dependent transcriptional activity has not been determined. Using an unbiased genetic approach that takes advantage of the evolutionary conservation of AR signaling, we have conducted a genome-wide RNAi screen in Drosophila cells for genes required for AR transcriptional activity and applied the results to human prostate cancer cells. We identified 45 AR-regulators, which include known pathway components and genes with functions not previously linked to AR regulation, such as HIPK2 (a protein kinase) and MED19 (a subunit of the Mediator complex). Depletion of HIPK2 and MED19 in human prostate cancer cells decreased AR target gene expression and, importantly, reduced the proliferation of androgen-dependent and castration-resistant prostate cancer cells. We also systematically analyzed additional Mediator subunits and uncovered a small subset of Mediator subunits that interpret AR signaling and affect AR-dependent transcription and prostate cancer cell proliferation. Importantly, targeting of HIPK2 by an FDA approved kinase inhibitor phenocopied the effect of depletion by RNAi and reduced the growth of AR-positive, but not AR negative, treatment-resistant prostate cancer cells. Thus, our screen has yielded new AR regulators including drugable targets that reduce the proliferation of castration-resistant prostate cancer cells. HIPK2 and MED19 were identified via a genome-wide RNAi screen as new androgen receptor (AR) reulators. Our goal in performing this microarray was to identify the gene regulated by HIPK2 and MED19 in a late stage prostate cancer cell line (LNCaP-abl), and to see what genes are in common with known genes to be regulated by AR, and what genes are unique to HIPK2 or MED19.
2013-01-30 | GSE43881 | GEO
Project description:Analysis of the role of Hipk2 in regulating gene expression in medullary thymic epithelial cells. The whole genome gene signatures of purified mTEC subsets (CD80 low, CD80 high) from TEC-specific Hipk2 knockout mice were compared to mating wildtype control mice (floxed, Cre-). Results provide the up- or down-regulated genes, affected by the Hipk2 gene knockout.
2015-01-05 | GSE63432 | GEO
Project description:The androgen receptor (AR) is a mediator of both androgen-dependent and castration- resistant prostate cancers. Identification of cellular factors affecting AR transcriptional activity could in principle yield new targets that reduce AR activity and combat prostate cancer, yet a comprehensive analysis of the genes required for AR-dependent transcriptional activity has not been determined. Using an unbiased genetic approach that takes advantage of the evolutionary conservation of AR signaling, we have conducted a genome-wide RNAi screen in Drosophila cells for genes required for AR transcriptional activity and applied the results to human prostate cancer cells. We identified 45 AR-regulators, which include known pathway components and genes with functions not previously linked to AR regulation, such as HIPK2 (a protein kinase) and MED19 (a subunit of the Mediator complex). Depletion of HIPK2 and MED19 in human prostate cancer cells decreased AR target gene expression and, importantly, reduced the proliferation of androgen-dependent and castration-resistant prostate cancer cells. We also systematically analyzed additional Mediator subunits and uncovered a small subset of Mediator subunits that interpret AR signaling and affect AR-dependent transcription and prostate cancer cell proliferation. Importantly, targeting of HIPK2 by an FDA approved kinase inhibitor phenocopied the effect of depletion by RNAi and reduced the growth of AR-positive, but not AR negative, treatment-resistant prostate cancer cells. Thus, our screen has yielded new AR regulators including drugable targets that reduce the proliferation of castration-resistant prostate cancer cells. HIPK2 and MED19 were identified via a genome-wide RNAi screen as new androgen receptor (AR) reulators. Our goal in performing this microarray was to identify the gene regulated by HIPK2 and MED19 in a late stage prostate cancer cell line (LNCaP-abl), and to see what genes are in common with known genes to be regulated by AR, and what genes are unique to HIPK2 or MED19. Knockdown of HIPK2 and MED19 was tested in LNCaP-abl cells against control. Each was performed in duplicates. Six samples were analyzed
2013-01-30 | E-GEOD-43881 | biostudies-arrayexpress
Project description:Analysis of the role of Hipk2 in regulating gene expression in medullary thymic epithelial cells. The whole genome gene signatures of purified mTEC subsets (CD80 low, CD80 high) from TEC-specific Hipk2 knockout mice were compared to mating wildtype control mice (floxed, Cre-). Results provide the up- or down-regulated genes, affected by the Hipk2 gene knockout. Total RNA obtained from isolated CD80 low and CD80 high mTECs of TEC-specific Hipk2 knockout mice compared to control mice mTEC subsets
2015-01-05 | E-GEOD-63432 | biostudies-arrayexpress
Project description:We used an integrated computational/experimental systems biology approach to identify upstream protein kinases that regulate gene expression changes in kidneys of HIV-1 transgenic mice (Tg26), which have significant tubulo-interstitial fibrosis (TIF) and glomerulosclerosis (GS). We identified the homeo-domain interacting protein kinase 2 (HIPK2) as a key regulator of TIF and GS. HIPK2 was upregulated in kidneys of Tg26 and patients with various kidney diseases. HIV infection increased the protein level of HIPK2 by promoting oxidative stress, which inhibited Siah1-mediated proteasomal degradation of HIPK2. The data contain two sets: kidney corticies from WT and Tg26 mice and HEK293 transfected with HIPK2, HIPK2-DN and wild type.
2012-02-01 | GSE35226 | GEO
Project description:HIPK2, a member of the homeodomain-interacting protein kinase family, is a transcriptional corepressor whose activity inhibits tumor progression and allows tumor cell apoptosis in response to chemotherapy. HIPK2 regulates the function of numerous molecules and its inhibition by siRNA, hypoxia or mutations, strongly favours molecular pathways involved in tumor progression, angiogenesis, invasion and chemoresistance. Hence the identification of novel molecules regulated by HIPK2 may be beneficial for better understanding tumor progression and for evaluating targeted antitumor therapies.
2011-12-31 | GSE31089 | GEO
Project description:HIPK2, a member of the homeodomain-interacting protein kinase family, is a transcriptional corepressor whose activity inhibits tumor progression and allows tumor cell apoptosis in response to chemotherapy. HIPK2 regulates the function of numerous molecules and its inhibition by siRNA, hypoxia or mutations, strongly favours molecular pathways involved in tumor progression, angiogenesis, invasion and chemoresistance. Hence the identification of novel molecules regulated by HIPK2 may be beneficial for better understanding tumor progression and for evaluating targeted antitumor therapies. By using microarray analysis, derived from HIPK2 overexpression (that mimics HIPK2 activation) in colon cancer RKO cells, we aim at evaluating the HIPK2 modulated gene expression involved in tumor progression.
2011-12-31 | E-GEOD-31089 | biostudies-arrayexpress
Project description:Homeodomain interacting protein kinase 2 (Hipk2) has previously been implicated in control of several transcription factors involved in embryonic development, apoptosis, cell proliferation and tumour development1–3. Analysis of gene expression in tissues from genetically heterogeneous mouse or human populations can reveal motifs associated with the structural or functional components of the tissue, and may predict roles for genes of unknown function4,5. Here we have applied this network strategy to uncover a novel role for the Hipk2 gene in the transcriptional system controlling adipogenesis. Both in vitro and in vivo models were used to show that knockdown or loss of Hipk2 specifically inhibits white adipose cell differentiation and tissue development. In addition, loss of Hipk2 leads to induction of pockets of multilocular brown fat-like cells in remaining white adipose depots. These cells express markers of brown and beige fat such as uncoupling protein 1 (Ucp1) and transmembrane protein 26 (Tmem26), and thermogenic genes including PPAR-γ coactivator 1a (Ppargc1a), and cell death-inducing DFFA-like effector a (Cidea). These changes are accompanied by increased insulin sensitivity in Hipk2 knock-out mice and reduced high fat diet-induced weight gain, highlighting a potential role for this kinase in diseases such as diabetes and obesity. Our study underscores the versatility and power of a readily available tissue, such as skin, for network modelling of systemic transcriptional programs involved in multiple pathways, including lipid metabolism and adipogenesis. Mammary fat pads from 115 distinct untreated 8 week old [FVB/N x Spret/Ei] x FVB/N Backcross mice
2014-01-01 | E-GEOD-46077 | biostudies-arrayexpress