Prospero homeobox 1 (PROX1) is a member of the homeobox transcription factor family that plays a critical role in the development of multiple tissues and specification of cell fate. PROX1 expression is differentially regulated based on the cellular context and plays an antagonistic role as a tumour promoter or suppressor in different tumour types. In human breast cancer, PROX1 expression is suppress-ed; however, the molecular mechanism by which it is down-regulated remains poorly understood. Here, we show that ectopic expression of PROX1 reduces the motility and invasiveness of MDA-MB-231 human breast cancer cells, suggesting that PROX1 functions as a negative regulator of tumour invasion in MDA-MB-231 cells. Treatment with histone deacetylase (HDAC) inhibitors up-regulates PROX1 mRNA and protein expression levels. Knockdown of HDAC1 using short hairpin RNA also up-regulates PROX1 mRNA and protein expression levels. We found that HDAC1 interacted with c-JUN at the activator protein (AP)-1-binding site located at -734 to -710 in the PROX1 promoter region to suppress PROX1 expression. In addition, c-JUN N-terminal kinase-mediated c-JUN phosphorylation was found to be crucial for silencing PROX1 expression. In conclusion, PROX1 expression can be silenced by the epigenetic mechanism involved in the complex formation of HDAC1 and c-JUN at the AP-1 site in the PROX1 promoter region in MDA-MB-231 human breast cancer cells. Therefore, this study revealed the epigenetic regulatory mechanism involved in the suppression of PROX1 expression in breast cancer cells.

• MeSH
• buňky MDA-MB-231 MeSH
• histondeacetylasa 1 genetika   metabolismus   MeSH
• homeoboxové geny MeSH
• homeodoménové proteiny * genetika   metabolismus   MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• nádorové buněčné linie MeSH
• nádory prsu * genetika   MeSH
• regulace genové exprese u nádorů MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ1 (retinoblastoma protein-interacting zinc finger gene 1) (PR) homologous domain containing (PRDM) transcription factors are expressed in neuronal and stem cell systems, and they exert multiple functions in a spatiotemporal manner. Therefore, it is believed that PRDM factors cooperate with a number of protein partners to regulate a critical set of genes required for maintenance of stem cell self-renewal and differentiation through genetic and epigenetic mechanisms. In this review, we summarize recent findings about the expression of PRDM factors and function in stem cell and neuronal systems with a focus on cofactor-dependent regulation of PRDM3/16 and FOG1/2. We put special attention on summarizing the effects of the PRDM proteins interaction with chromatin modulators (NuRD complex and CtBPs) on the stem cell characteristic and neuronal differentiation. Although PRDM factors are known to possess intrinsic enzyme activity, our literature analysis suggests that cofactor-dependent regulation of PRDM3/16 and FOG1/2 is also one of the important mechanisms to orchestrate bidirectional target gene regulation. Therefore, determining stem cell and neuronal-specific cofactors will help better understanding of PRDM3/16 and FOG1/2-controlled stem cell maintenance and neuronal differentiation. Finally, we discuss the clinical aspect of these PRDM factors in different diseases including cancer. Overall, this review will help further sharpen our knowledge of the function of the PRDM3/16 and FOG1/2 with hopes to open new research fields related to these factors in stem cell biology and neuroscience.

• MeSH
• buněčná diferenciace MeSH
• chromatin metabolismus   MeSH
• DNA vazebné proteiny metabolismus   MeSH
• jaderné proteiny metabolismus   MeSH
• kmenové buňky cytologie   metabolismus   MeSH
• komplex Mi2-NuRD metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• myši MeSH
• neurony metabolismus   MeSH
• neurovědy MeSH
• protein MDS1 and EVI1 complex locus metabolismus   MeSH
• protein PRDI-BF1 metabolismus   MeSH
• proteinové domény MeSH
• regulace genové exprese * MeSH
• riziko MeSH
• transkripční faktory metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Although histone acetylation is one of the most widely studied epigenetic modifications, there is still a lack of information regarding how the acetylome is regulated during brain development and pathophysiological processes. We demonstrate that the embryonic brain (E15) is characterized by an increase in H3K9 acetylation as well as decreases in the levels of HDAC1 and HDAC3. Moreover, experimental induction of H3K9 hyperacetylation led to the overexpression of NCAM in the embryonic cortex and depletion of Sox2 in the subventricular ependyma, which mimicked the differentiation processes. Inducing differentiation in HDAC1-deficient mouse ESCs resulted in early H3K9 deacetylation, Sox2 downregulation, and enhanced astrogliogenesis, whereas neuro-differentiation was almost suppressed. Neuro-differentiation of (wt) ESCs was characterized by H3K9 hyperacetylation that was associated with HDAC1 and HDAC3 depletion. Conversely, the hippocampi of schizophrenia-like animals showed H3K9 deacetylation that was regulated by an increase in both HDAC1 and HDAC3. The hippocampi of schizophrenia-like brains that were treated with the cannabinoid receptor-1 inverse antagonist AM251 expressed H3K9ac at the level observed in normal brains. Together, the results indicate that co-regulation of H3K9ac by HDAC1 and HDAC3 is important to both embryonic brain development and neuro-differentiation as well as the pathophysiology of a schizophrenia-like phenotype.

• MeSH
• acetylace MeSH
• antagonisté kanabinoidních receptorů farmakologie   MeSH
• antipsychotika farmakologie   MeSH
• časové faktory MeSH
• epigeneze genetická MeSH
• gestační stáří MeSH
• histondeacetylasa 1 antagonisté a inhibitory   genetika   metabolismus   MeSH
• histondeacetylasy genetika   metabolismus   MeSH
• histony metabolismus   MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• methylazoxymethanolacetát MeSH
• modely nemocí na zvířatech MeSH
• molekuly buněčné adheze nervové genetika   metabolismus   MeSH
• mozek účinky léků   embryologie   enzymologie   patologie   MeSH
• myši inbrední C57BL MeSH
• neurogeneze * účinky léků   MeSH
• neurony účinky léků   enzymologie   patologie   MeSH
• posttranslační úpravy proteinů MeSH
• potkani Sprague-Dawley MeSH
• receptor kanabinoidní CB1 antagonisté a inhibitory   metabolismus   MeSH
• schizofrenie chemicky indukované   farmakoterapie   enzymologie   genetika   MeSH
• signální transdukce MeSH
• transkripční faktory SOXB1 genetika   metabolismus   MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Butyrate, a short-chain fatty acid produced by fermentation of dietary fiber, is an important regulator of colonic epithelium homeostasis. In this study, we investigated the impact of this histone deacetylase (HDAC) inhibitor on expression/activity of cytochrome P450 family 1 (CYP1) and on metabolism of carcinogenic polycyclic aromatic hydrocarbon, benzo[a]pyrene (BaP), in colon epithelial cells. Sodium butyrate (NaBt) strongly potentiated the BaP-induced expression of CYP1A1 in human colon carcinoma HCT116 cells. It also co-stimulated the 7-ethoxyresorufin-O-deethylase (EROD) activity induced by the 2,3,7,8-tetrachlorodibenzo-p-dioxin, a prototypical ligand of the aryl hydrocarbon receptor. Up-regulation of CYP1A1 expression/activity corresponded with an enhanced metabolism of BaP and formation of covalent DNA adducts. NaBt significantly potentiated CYP1A1 induction and/or metabolic activation of BaP also in other human colon cell models, colon adenoma AA/C1 cells, colon carcinoma HT-29 cells, or in NCM460D cell line derived from normal colon mucosa. Our results suggest that the effects of NaBt were due to its impact on histone acetylation, because additional HDAC inhibitors (trichostatin A and suberanilohydroxamic acid) likewise increased both the induction of EROD activity and formation of covalent DNA adducts. NaBt-induced acetylation of histone H3 (at Lys14) and histone H4 (at Lys16), two histone modifications modulated during activation of CYP1A1 transcription, and it reduced binding of HDAC1 to the enhancer region of CYP1A1 gene. This in vitro study suggests that butyrate, through modulation of histone acetylation, may potentiate induction of CYP1A1 expression, which might in turn alter the metabolism of BaP within colon epithelial cells.

• MeSH
• adukty DNA účinky léků   metabolismus   MeSH
• benzopyren metabolismus   farmakokinetika   MeSH
• beta-katenin metabolismus   MeSH
• buňky HT-29 MeSH
• cytochrom P-450 CYP1A1 genetika   metabolismus   MeSH
• HCT116 buňky MeSH
• histondeacetylasa 1 antagonisté a inhibitory   metabolismus   MeSH
• histony metabolismus   MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• kolon účinky léků   metabolismus   MeSH
• kyselina máselná farmakologie   MeSH
• lidé MeSH
• metabolická inaktivace MeSH
• zesilovače transkripce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

DNA damage response (DDR) in ribosomal genes and mechanisms of DNA repair in embryonic stem cells (ESCs) are less explored nuclear events. DDR in ESCs should be unique due to their high proliferation rate, expression of pluripotency factors, and specific chromatin signature. Given short population doubling time and fast progress through G1 phase, ESCs require a sustained production of rRNA, which leads to the formation of large and prominent nucleoli. Although transcription of rRNA in the nucleolus is relatively well understood, little is known about DDR in this nuclear compartment. Here, we directed formation of double-strand breaks in rRNA genes with I- PpoI endonuclease, and we studied nucleolar morphology, DDR, and chromatin modifications. We observed a pronounced formation of I- PpoI-induced nucleolar caps, positive on BRCA1, NBS1, MDC1, γH2AX, and UBF1 proteins. We showed interaction of nucleolar protein TCOF1 with HDAC1 and TCOF1 with CARM1 after DNA injury. Moreover, H3R17me2a modification mediated by CARM1 was found in I- PpoI-induced nucleolar caps. Finally, we report that heterochromatin protein 1 is not involved in DNA repair of nucleolar caps.

• MeSH
• acetylace MeSH
• arginin metabolismus   MeSH
• buněčné jadérko genetika   ultrastruktura   MeSH
• buněčné linie MeSH
• dvouřetězcové zlomy DNA * MeSH
• embryonální kmenové buňky metabolismus   ultrastruktura   MeSH
• fosfoproteiny metabolismus   MeSH
• geny rRNA MeSH
• histondeacetylasa 1 metabolismus   MeSH
• histony metabolismus   MeSH
• jaderné proteiny metabolismus   MeSH
• metylace MeSH
• myši MeSH
• oprava DNA MeSH
• proteinarginin-N-methyltransferasy metabolismus   MeSH
• RNA ribozomální genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-β (TGF-β) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-β target genes, thereby limiting pro-fibrotic TGF-β effects. Even though temporary upregulation of TGF-β in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-β signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-β signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.

• MeSH
• alkoholická cirhóza jater metabolismus   patologie   MeSH
• dospělí MeSH
• fibroblasty metabolismus   MeSH
• fibróza MeSH
• histondeacetylasa 1 metabolismus   MeSH
• histondemethylasy metabolismus   MeSH
• hojení ran MeSH
• idiopatická plicní fibróza metabolismus   patologie   MeSH
• jaderné receptory - podrodina 4, skupina A, člen 1 genetika   metabolismus   fyziologie   MeSH
• játra metabolismus   patologie   MeSH
• korepresorové proteiny metabolismus   MeSH
• kultivované buňky MeSH
• kůže cytologie   metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• myši knockoutované MeSH
• myši MeSH
• plíce metabolismus   patologie   MeSH
• represorové proteiny metabolismus   MeSH
• senioři MeSH
• signální transdukce MeSH
• studie případů a kontrol MeSH
• systémová sklerodermie metabolismus   patologie   MeSH
• transformující růstový faktor beta metabolismus   MeSH
• transkripční faktor Sp1 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Valproic acid (VPA) is a wide spread anticonvulsant and mood-stabilizing agent, the use of which is associated with hepatotoxicity, bone marrow suppression and osteomalacia. In the current paper we propose a possible mechanism of VPA-induced osteomalacia involving accelerated catabolism of 1α,25(OH)(2)-vitamin D3 (VD3) due to increased expression of CYP24. We demonstrate that VPA strongly potentiates CYP24 mRNA expression by VD3 in human hepatocytes (HH) and in human embryonic kidney cells (HEK293). By the method of gene reporter assay we found that VPA increases basal and VD3-inducible activity of CYP24 promoter (pCYP24-luc) in human liver adenocarcinoma (HepG2) and in HEK293 cells in dose-dependent manner. In order to delineate the role of inhibitory effects of VPA on histone deacetylase 1 (HDAC1), we compared the effects of VPA with trichostatin A (TSA) on basal and inducible levels of CYP24 mRNA and pCYP24-luc transactivation. Transactivation of CYP24 promoter by VD3 was enhanced in the presence of both TSA and VPA. In contrast, VD3-inducible expression of CYP24 mRNA was enhanced by VPA but not by TSA, implying that HDAC1 inhibition is not the major reason for VPA effects on CYP24. We examined the effects of VPA on mitogen-activated protein kinases as the important transcriptional regulators of VDR. VPA activated extracellular signal-regulated kinase (ERK) but not c-Jun-N-terminal kinase (JNK) and p38 MAPKs. In conclusion, VPA enhances transcriptional activity of VDR and increases expression of CYP24 mRNA in the presence of VD3 in physiological concentrations. The mechanism involves activation of ERK and partly the inhibition of HDAC1.

• MeSH
• antikonvulziva toxicita   MeSH
• cholekalciferol farmakologie   MeSH
• extracelulárním signálem regulované MAP kinasy genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• hepatocyty účinky léků   MeSH
• histondeacetylasa 1 biosyntéza   genetika   MeSH
• kyselina valproová toxicita   MeSH
• lidé MeSH
• luciferasy genetika   MeSH
• messenger RNA biosyntéza   genetika   MeSH
• osteomalacie chemicky indukované   patologie   MeSH
• plazmidy genetika   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• receptory kalcitriolu účinky léků   MeSH
• steroidhydroxylasy biosyntéza   genetika   MeSH
• steroidní receptory účinky léků   MeSH
• transfekce MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

There is increasing evidence to suggest that splicing decisions are largely made when the nascent RNA is still associated with chromatin. Here we demonstrate that activity of histone deacetylases (HDACs) influences splice site selection. Using splicing-sensitive microarrays, we identified ∼700 genes whose splicing was altered after HDAC inhibition. We provided evidence that HDAC inhibition induced histone H4 acetylation and increased RNA Polymerase II (Pol II) processivity along an alternatively spliced element. In addition, HDAC inhibition reduced co-transcriptional association of the splicing regulator SRp40 with the target fibronectin exon. We further showed that the depletion of HDAC1 had similar effect on fibronectin alternative splicing as global HDAC inhibition. Importantly, this effect was reversed upon expression of mouse HDAC1 but not a catalytically inactive mutant. These results provide a molecular insight into a complex modulation of splicing by HDACs and chromatin modifications.

• MeSH
• alternativní sestřih účinky léků   genetika   fyziologie   MeSH
• HeLa buňky MeSH
• histondeacetylasa 1 genetika   fyziologie   MeSH
• histondeacetylasy genetika   metabolismus   fyziologie   MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• jaderné proteiny genetika   MeSH
• kultivované buňky MeSH
• lidé MeSH
• mikročipová analýza MeSH
• myši MeSH
• proteiny vázající RNA genetika   MeSH
• regulace genové exprese účinky léků   MeSH
• stanovení celkové genové exprese MeSH
• transfekce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Aim. This study was designed to examine whether the class I and class IIa histone deacetylase (HDAC) inhibitors, sodium butyrate and sodium valproate alter the expression of human NCOR1 and/or NCOR2 genes coding for N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator for retinoid and thyroid hormone receptors), respectively. Methods. Human leukemia HL-60 cells were treated for 24 h with 0.5 and 1 mM sodium butyrate, 1 to 3 mM sodium valproate, 1 mcM all-trans retinoic acid (ATRA) or cotreated with 1 mcM ATRA and 0.5 mM sodium butyrate. The acetylation of histones H3 and H4 was analysed by western blotting. The levels of NCOR1 and NCOR2 mRNA were determined by quantitative real-time PCR. Expression of NCF2 gene coding for the NADPH oxidase subunit p67phox was evaluated as a marker of myeloid differentiation. Results. Both butyrate and valproate increased the acetylation of histone H3 at Lys9 and/or Lys14 as well as histone H4 at Lys12. Both HDAC inhibitors caused a significant increase in NCF2 mRNA levels without affecting NCOR1 or NCOR2 mRNA levels. Similarly, ATRA alone or in combination with butyrate induced NCF2 gene expression without any significant influence on the expression of NCOR1 or NCOR2 genes. Conclusion. We conclude that inhibitors of class I and class IIa HDACs do not alter the expression of human NCOR1 or NCOR2 genes and that the onset of myeloid differentiation is not accompanied by induction or repression of these genes in HL-60 cells.

• MeSH
• aktivace transkripce genetika   účinky léků   MeSH
• butyráty antagonisté a inhibitory   metabolismus   MeSH
• financování organizované MeSH
• genetické techniky využití   MeSH
• histondeacetylasa 1 farmakokinetika   MeSH
• histondeacetylasa 2 farmakokinetika   MeSH
• HL-60 buňky imunologie   metabolismus   MeSH
• korepresorové proteiny genetika   imunologie   metabolismus   MeSH
• kyselina valproová analogy a deriváty   antagonisté a inhibitory   metabolismus   MeSH
• receptory cytoplazmatické a nukleární farmakokinetika   MeSH

In response to ionizing radiation (IR), cells delay cell cycle progression and activate DNA repair. Both processes are vital for genome integrity, but the mechanisms involved in their coordination are not fully understood. In a mass spectrometry screen, we identified the adenosine triphosphate-dependent chromatin-remodeling protein CHD4 (chromodomain helicase DNA-binding protein 4) as a factor that becomes transiently immobilized on chromatin after IR. Knockdown of CHD4 triggers enhanced Cdc25A degradation and p21(Cip1) accumulation, which lead to more pronounced cyclin-dependent kinase inhibition and extended cell cycle delay. At DNA double-strand breaks, depletion of CHD4 disrupts the chromatin response at the level of the RNF168 ubiquitin ligase, which in turn impairs local ubiquitylation and BRCA1 assembly. These cell cycle and chromatin defects are accompanied by elevated spontaneous and IR-induced DNA breakage, reduced efficiency of DNA repair, and decreased clonogenic survival. Thus, CHD4 emerges as a novel genome caretaker and a factor that facilitates both checkpoint signaling and repair events after DNA damage.

• MeSH
• autoantigeny genetika   metabolismus   MeSH
• buněčný cyklus genetika   MeSH
• CDC geny MeSH
• chromatin * genetika   metabolismus   MeSH
• chromozomy metabolismus   MeSH
• DNA genetika   metabolismus   MeSH
• dvouřetězcové zlomy DNA MeSH
• fosfatasy cdc25 genetika   metabolismus   MeSH
• ionizující záření MeSH
• komplex Mi2-NuRD genetika   metabolismus   MeSH
• lidé MeSH
• malá interferující RNA metabolismus   farmakologie   MeSH
• nádorové buněčné linie MeSH
• oprava DNA * MeSH
• poškození DNA * fyziologie   MeSH
• RNA interference MeSH
• signální transdukce * genetika   MeSH
• ubikvitin genetika   metabolismus   MeSH
• ubikvitinace MeSH
• Check Tag
• lidé MeSH