RESUMO
BACKGROUND: Major depression has a complex and multifactorial etiology constituted by the interaction between genetic and environmental factors in its development. OBJECTIVE: The aim of this study was to evaluate the effects of sodium butyrate (SD) on epigenetic enzyme alterations in rats subjected to animal models of depression induced by maternal deprivation (MD) or chronic mild stress (CMS). METHODS: To induce MD, male Wistar rats were deprived of maternal care during the first 10 days of life. To induce CMS, rats were subjected to the CMS for 40 days. Adult rats were then treated with daily injections of SD for 7 days. Animals were subjected to the forced swimming test (FST), and then, histone deacetylase (HDAC), histone acetyltransferase (HAT), and DNA methyltransferase (DNMT) activities were evaluated in the brain. RESULTS: MD and CMS increased immobility time in FST and increased HDAC and DNMT activity in the animal brains. SD reversed increased immobility induced by both animal models and the alterations in HDAC and DNMT activities. There was a positive correlation between enzyme activities and immobility time for both models. HDAC and DNMT activities also presented a positive correlation between themselves. CONCLUSION: These results suggest that epigenetics can play an important role in major depression pathophysiology triggered by early or late life stress and its treatment.
Assuntos
Antidepressivos , Encéfalo , Ácido Butírico , Epigênese Genética , Privação Materna , Ratos Wistar , Estresse Psicológico , Animais , Masculino , Estresse Psicológico/tratamento farmacológico , Ácido Butírico/farmacologia , Ácido Butírico/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ratos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Histona Desacetilases/metabolismo , Depressão/tratamento farmacológico , Histona Acetiltransferases/metabolismo , Natação/psicologiaRESUMO
Fibrosis is a condition characterized by the excessive accumulation of extracellular matrix proteins in tissues, leading to organ dysfunction and failure. Recent studies have identified EP300, a histone acetyltransferase, as a crucial regulator of the epigenetic changes that contribute to fibrosis. In fact, EP300-mediated acetylation of histones alters global chromatin structure and gene expression, promoting the development and progression of fibrosis. Here, we review the role of EP300-mediated epigenetic regulation in multi-organ fibrosis and its potential as a therapeutic target. We discuss the preclinical evidence that suggests that EP300 inhibition can attenuate fibrosis-related molecular processes, including extracellular matrix deposition, inflammation, and epithelial-to-mesenchymal transition. We also highlight the contributions of small molecule inhibitors and gene therapy approaches targeting EP300 as novel therapies against fibrosis.
Assuntos
Epigênese Genética , Histonas , Humanos , Fibrose , Histonas/metabolismo , Matriz Extracelular/metabolismo , Histona Acetiltransferases/metabolismo , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismoRESUMO
BACKGROUND: Alpaca (Vicugna pacos), llama (Lama glama), vicugna (Vicugna vicugna) and guanaco (Lama guanicoe), are the camelid species distributed over the Andean high-altitude grasslands, the Altiplano, and the Patagonian arid steppes. Despite the wide interest on these animals, most of the loci under selection are still unknown. Using whole-genome sequencing (WGS) data we investigated the occurrence and the distribution of Runs Of Homozygosity (ROHs) across the South American Camelids (SACs) genome to identify the genetic relationship between the four species and the potential signatures of selection. RESULTS: A total of 37 WGS samples covering the four species was included in the final analysis. The multi-dimensional scaling approach showed a clear separation between the four species; however, admixture analysis suggested a strong genetic introgression from vicugna and llama to alpaca. Conversely, very low genetic admixture of the guanaco with the other SACs was found. The four species did not show significant differences in the number, length of ROHs (100-500 kb) and genomic inbreeding values. Longer ROHs (> 500 kb) were found almost exclusively in alpaca. Seven overlapping ROHs were shared by alpacas, encompassing nine loci (FGF5, LOC107034918, PRDM8, ANTXR2, LOC102534792, BSN, LOC116284892, DAG1 and RIC8B) while nine overlapping ROHs were found in llama with twenty-five loci annotated (ERC2, FZD9, BAZ1B, BCL7B, LOC116284208, TBL2, MLXIPL, PHF20, TRNAD-AUC, LOC116284365, RBM39, ARFGEF2, DCAF5, EXD2, HSPB11, LRRC42, LDLRAD1, TMEM59, LOC107033213, TCEANC2, LOC102545169, LOC116278408, SMIM15, NDUFAF2 and RCOR1). Four overlapping ROHs, with three annotated loci (DLG1, KAT6B and PDE4D) and three overlapping ROHs, with seven annotated genes (ATP6V1E1, BCL2L13, LOC116276952, BID, KAT6B, LOC116282667 and LOC107034552), were detected for vicugna and guanaco, respectively. CONCLUSIONS: The signatures of selection revealed genomic areas potentially selected for production traits as well as for natural adaptation to harsh environment. Alpaca and llama hint a selection driven by environment as well as by farming purpose while vicugna and guanaco showed selection signals for adaptation to harsh environment. Interesting, signatures of selection on KAT6B gene were identified for both vicugna and guanaco, suggesting a positive effect on wild populations fitness. Such information may be of interest to further ecological and animal production studies.
Assuntos
Camelídeos Americanos , Animais , Humanos , Camelídeos Americanos/genética , Grupos Raciais , Aclimatação , Agricultura , América do Sul , Receptores de Peptídeos , Fatores de Transcrição , Histona AcetiltransferasesRESUMO
BACKGROUND: To date, the main clinical interest in DPP4 is focused on its inhibition in diabetic patients to prolong the half-life of incretins. Epigenetic alterations resulting from DPP4 inhibition have been poorly explored. OBJECTIVE: The objective of this study was to determine, whether sitagliptin, a DPP4 inhibitor, has effects on the expression of KAT7 and SIRT1 (genes encoding a histone acetyltransferase and a histone deacetylase, respectively) in MCF7 breast cancer cells, which play an essential role in modulating the epigenetic landscape of chromatin. MATERIAL AND METHODS: MCF7 cells were incubated for 20 h with sitagliptin at concentrations of 0.5, 1.0 and 2.0 µM. Total RNA was isolated and the relative mRNA expression of KAT7 and SIRT1 was determined by RT-qPCR. RESULTS: There was downregulation in the relative expression of both genes; for KAT7, downregulation reached up to 0.49 (p = 0.027) and for SIRT1, it reached up to 0.55 (p = 0.037). CONCLUSIONS: These results suggest that sitagliptin has effects on the histone epigenetic landscape. This topic deserves further study due to the current sample use of DPP4 inhibitors in diabetic patients.
ANTECEDENTES: Hasta la fecha, el principal interés clínico de la DPP4 se centra en su inhibición en pacientes diabéticos para prolongar la vida media de las incretinas. Las alteraciones epigenéticas resultantes de la inhibición de DPP4 han sido poco exploradas. OBJETIVO: Determinar si la sitagliptina, un inhibidor de DPP4, tiene efectos sobre la expresión de KAT7 y SIRT1 (genes que codifican una histona acetiltransferasa y una histona desacetilasa, respectivamente) en células de cáncer de mama MCF7, que desempeñan un papel esencial en la modulación del paisaje epigenético de la cromatina. MÉTODO: Las células MCF7 se incubaron durante 20 h con sitagliptina a concentraciones de 0.5, 1.0 y 2.0 µM. Se aisló el ARN total y se determinó la expresión relativa de ARNm de KAT7 y SIRT1 mediante RT-qPCR. RESULTADOS: Hubo una regulación a la baja en la expresión relativa de ambos genes; para KAT7, la regulación negativa alcanzó hasta 0.49 (p = 0.027) y para SIRT1 alcanzó hasta 0.55 (p = 0.037). CONCLUSIONES: Estos resultados sugieren que la sitagliptina tiene efectos sobre el paisaje epigenético de las histonas. Este tema merece más estudios debido al uso actual de inhibidores de DPP4 en pacientes diabéticos.
Assuntos
Neoplasias da Mama , Fosfato de Sitagliptina , Humanos , Feminino , Fosfato de Sitagliptina/farmacologia , Regulação para Baixo , Sirtuína 1/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Dipeptidil Peptidase 4 , Células MCF-7 , Expressão Gênica , Histona Acetiltransferases/genéticaRESUMO
Acetylation signaling pathways in trypanosomatids, a group of early branching organisms, are poorly understood due to highly divergent protein sequences. To overcome this challenge, we used interactomic datasets and AlphaFold2 (AF2)-multimer to predict direct interactions and validated them using yeast two and three-hybrid assays. We focused on MORF4 related gene (MRG) domain-containing proteins and their interactions, typically found in histone acetyltransferase/deacetylase complexes. The results identified a structurally conserved complex, TcTINTIN, which is orthologous to human and yeast trimer independent of NuA4 for transcription interaction (TINTIN) complexes; and another trimeric complex involving an MRG domain, only seen in trypanosomatids. The identification of a key component of TcTINTIN, TcMRGBP, would not have been possible through traditional homology-based methods. We also conducted molecular dynamics simulations, revealing a conformational change that potentially affects its affinity for TcBDF6. The study also revealed a novel way in which an MRG domain participates in simultaneous interactions with two MRG binding proteins binding two different surfaces, a phenomenon not previously reported. Overall, this study demonstrates the potential of using AF2-processed interactomic datasets to identify protein complexes in deeply branched eukaryotes, which can be challenging to study based on sequence similarity. The findings provide new insights into the acetylation signaling pathways in trypanosomatids, specifically highlighting the importance of MRG domain-containing proteins in forming complexes, which may have important implications for understanding the biology of these organisms and developing new therapeutics. On the other hand, our validation of AF2 models for the determination of multiprotein complexes illuminates the power of using such artificial intelligence-derived tools in the future development of biology.
Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Humanos , Inteligência Artificial , Furilfuramida , Núcleo Celular/metabolismo , Proteínas , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Histona Acetiltransferases/genéticaRESUMO
Chemoresistance is associated with tumor recurrence, metastases, and short survival. Cisplatin is one of the most used chemotherapies in cancer treatment, including head and neck squamous cell carcinoma (HNSCC), and many patients develop resistance. Here, we established cell lines resistant to cisplatin to better understand epigenetics and biological differences driving the progression of HNSCC after treatment. Cisplatin resistance was established in CAL-27 and SCC-9 cell lines. Gene expression of HDAC1, HDAC2, SIRT1, MTA1, KAT2B, KAT6A, KAT6B, and BRD4 indicated the cisplatin activates the epigenetic machinery. Increases in tumor aggressiveness were detected by BMI-1 and KI-67 in more resistant cell lines. Changes in cellular shape and epithelial-mesenchymal transition (EMT) activation were also observed. HDAC1 and ZEB1 presented an opposite distribution with down-regulation of HDAC1 and up-regulation of ZEB1 in the course of chemoresistance. Up-regulation of ZEB1 and BMI-1 in patients with HNSCC is also associated with a poor response to therapy. Cancer stem cells (CSC) population increased significantly with chemoresistance. Down-regulation of HDAC1, HDAC2, and SIRT1 and accumulation of Vimentin and ZEB1 were observed in the CSC population. Our results suggest that in the route to cisplatin chemoresistance, epigenetic modifications can be associated with EMT activation and CSC accumulation which originate more aggressive tumors.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Cisplatino/farmacologia , Sirtuína 1/genética , Sirtuína 1/metabolismo , Sirtuína 1/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Transição Epitelial-Mesenquimal/genética , Proteínas Nucleares/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Histona Acetiltransferases/metabolismoRESUMO
Congenital anomalies (CA) affect 3-5% of newborns, representing the second-leading cause of infant mortality in Argentina. Multiple congenital anomalies (MCA) have a prevalence of 2.26/1000 births in newborns, while congenital heart diseases (CHD) are the most frequent CA with a prevalence of 4.06/1000 births. The aim of this study was to identify the genetic causes in Argentinian patients with MCA and isolated CHD. We recruited 366 patients (172 with MCA and 194 with isolated CHD) born between June 2015 and August 2019 at public hospitals. DNA from peripheral blood was obtained from all patients, while karyotyping was performed in patients with MCA. Samples from patients presenting conotruncal CHD or DiGeorge phenotype (n = 137) were studied using MLPA. Ninety-three samples were studied by array-CGH and 18 by targeted or exome next-generation sequencing (NGS). A total of 240 patients were successfully studied using at least one technique. Cytogenetic abnormalities were observed in 13 patients, while 18 had clinically relevant imbalances detected by array-CGH. After MLPA, 26 patients presented 22q11 deletions or duplications and one presented a TBX1 gene deletion. Following NGS analysis, 12 patients presented pathogenic or likely pathogenic genetic variants, five of them, found in KAT6B, SHH, MYH11, MYH7 and EP300 genes, are novel. Using an algorithm that combines molecular techniques with clinical and genetic assessment, we determined the genetic contribution in 27.5% of the analyzed patients.
Assuntos
Anormalidades Múltiplas , Cardiopatias Congênitas , Anormalidades Múltiplas/genética , Algoritmos , Testes Genéticos , Cardiopatias Congênitas/genética , Histona Acetiltransferases , Humanos , CariotipagemRESUMO
Acetylation is a reversible post-translational modification (PTM) that regulates important cellular processes such as proliferation, DNA damage repair and cell cycle progress. When the balance is broken, these processes are affected and lead to carcinogenesis. Therefore, the study of acetylation has led to its proposal as a target pathway for anticancer therapies. Here, we discuss how acetylation regulates the cell cycle process, how it is modified in cancer cells and which are the key proteins in the regulation of apoptosis induction in cancer cells that can become targets to fight cancer. The inhibition of acetylation has been proposed as an emergent therapy against cancer, compounds such as 6-Penthadecyl salicylic acid, Curcumin, Garcinol and C646, among others, are currently studied because they show antitumor activity related to the inhibition of acetylation. Recently, the use of the acetylomics research tool has improved the study of acetylation as a target against tumor cells, but still the thresholds between promoting DNA instability and regulating gene expression by acetylation are not clear in many cell types.
Assuntos
Histona Acetiltransferases , Neoplasias , Acetilação , Reparo do DNA , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Processamento de Proteína Pós-TraducionalRESUMO
Epigenetic mechanisms are responsible for a wide range of biological phenomena in insects, controlling embryonic development, growth, aging and nutrition. Despite this, the role of epigenetics in shaping insect-pathogen interactions has received little attention. Gene expression in eukaryotes is regulated by histone acetylation/deacetylation, an epigenetic process mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this study, we explored the role of the Aedes aegypti histone acetyltransferase CBP (AaCBP) after infection with Zika virus (ZIKV), focusing on the two main immune tissues, the midgut and fat body. We showed that the expression and activity of AaCBP could be positively modulated by blood meal and ZIKV infection. Nevertheless, Zika-infected mosquitoes that were silenced for AaCBP revealed a significant reduction in the acetylation of H3K27 (CBP target marker), followed by downmodulation of the expression of immune genes, higher titers of ZIKV and lower survival rates. Importantly, in Zika-infected mosquitoes that were treated with sodium butyrate, a histone deacetylase inhibitor, their capacity to fight virus infection was rescued. Our data point to a direct correlation among histone hyperacetylation by AaCBP, upregulation of antimicrobial peptide genes and increased survival of Zika-infected-A. aegypti.