Divergent functions of histone acetyltransferases KAT2A and KAT2B in keratinocyte self-renewal and differentiation.

The mammalian epidermis undergoes constant renewal, replenished by a pool of stem cells and terminal differentiation of their progeny. This is accompanied by changes in gene expression and morphology that are orchestrated, in part, by epigenetic modifiers. Here, we define the role of the histone acetyltransferase KAT2A in epidermal homeostasis and provide a comparative analysis that reveals key functional divergence with its paralog KAT2B. In contrast to the reported function of KAT2B in epidermal differentiation, KAT2A supports the undifferentiated state in keratinocytes. RNA-seq analysis of KAT2A- and KAT2B- depleted keratinocytes revealed dysregulated epidermal differentiation. Depletion of KAT2A led to premature expression of epidermal differentiation genes in the absence of inductive signals, whereas loss of KAT2B delayed differentiation. KAT2A acetyltransferase activity was indispensable in regulating epidermal differentiation gene expression. The metazoan-specific N terminus of KAT2A was also required to support its function in keratinocytes. We further showed that the interplay between KAT2A- and KAT2B-mediated regulation was important for normal cutaneous wound healing in vivo. Overall, these findings reveal a distinct mechanism in which keratinocytes use a pair of highly homologous histone acetyltransferases to support divergent functions in self-renewal and differentiation processes.

The interaction between the histone acetyltransferase complex Hat1-Hat2 and transcription factor AmyR provides a molecular brake to regulate amylase gene expression.

The chromatin structure is generally regulated by chromatin remodelers and histone modifiers, which affect DNA replication, repair, and levels of transcription. The first identified histone acetyltransferase was Hat1/KAT1, which belongs to lysine (K) acetyltransferases. The catalytic subunit Hat1 and the regulatory subunit Hat2 make up the core HAT1 complex. In this study, the results of tandem affinity purification and mass spectrometry and bimolecular fluorescence complementation proved that the Penicillium oxalicum PoHat1-Hat2 is the transcriptional cofactor of the sequence-specific transcription factor PoAmyR, a transcription activator essential for the transcription of amylase gene. ChIP-qPCR results demonstrated that the complex PoHat1-Hat2 is recruited by PoAmyR to the promoters of prominent amylase genes Poamy13A and Poamy15A and performs histone H4 lysine12 acetylation. The result of the yeast two-hybrid test indicated that PoHat2 is the subunit that directly interacts with PoAmyR. PoHat1-Hat2 acts as the molecular brake of the PoAmyR-regulating transcription of amylase genes. A putative model for amylase gene regulation by PoAmyR-Hat2-Hat1 was constructed. Our paper is the first report that the Hat1-Hat2 complex acts as a cofactor for sequence-specific TF to regulate gene expression and explains the mechanism of TF AmyR regulating amylase genes expression.

Histone acetyltransferases derived RW20 protects and promotes rapid clearance of Pseudomonas aeruginosa in zebrafish larvae.

Pseudomonas is a group of bacteria that can cause a wide range of infections, particularly in people with weakened immune systems, such as those with cystic fibrosis or who are hospitalized. It can also cause infections in the skin and soft tissue, including cellulitis, abscesses and wound infections. Antimicrobial peptides (AMPS) are the alternative strategy due to their broad spectrum of activity and act as effective treatment against multi-drug resistance pathogens. In this study, we have used an AMP, RW20 (1RPVKRKKGWPKGVKRGPPKW20). RW20 peptide is derived from the histone acetyltransferases (HATs) of the freshwater teleost, Channa striatus. The antimicrobial prediction tool has been utilized to identify the RW20 sequence from the HATs sequence. We synthesized the peptide to explore its mechanism of action. In an in vitro assay, RW20 was challenged against P. aeruginosa and we showed that RW20 displayed antibacterial properties and damaged the cell membrane. The mechanism of action of RW20 against P. aeruginosa has been established via field emission scanning electron microscopy (FESEM) as well as fluorescence assisted cell sorter (FACS) analysis. Both these experiments established that RW20 caused bacterial membrane disruption and cell death. Moreover, the impact of RW20, in-vivo, was tested against P. aeruginosa-infected zebrafish larvae. In the infected larvae, RW20 showed protective effect against P. aeruginosa by increasing the larval antioxidant enzymes, reducing the excess oxidative stress and apoptosis. Thus, it is possible that HATs-derived RW20 can be an efficient antimicrobial molecule against P. aeruginosa.

Discovery of novel nucleoside derivatives as selective lysine acetyltransferase p300 inhibitors for cancer therapy.

P300 and CBP are two closely related histone acetyltransferases that are important transcriptional coactivators of many cellular processes. Inhibition of the transcriptional regulator p300/CBP is a promising therapeutic approach in oncology. However, there are no reported single selective p300 or CBP inhibitors to date. In this study, we designed and optimized a series of lysine acetyltransferase p300 selective inhibitors bearing a nucleoside scaffold. Most compounds showed excellent inhibitory activity against p300 with IC50 ranging from 0.18 to 9.90 µM, except for J16, J29, J40, and J48. None of the compounds showed inhibitory activity against CBP (inhibition rate < 50 % at 10 µM). Then the cytotoxicity of the compounds against a series of cancer cells were evaluated. Compounds J31 and J32 showed excellent proliferation inhibitory activity on cancer cells T47D and H520 with desirable selectivity profile of p300 over CBP. These compounds could be promising lead compounds for the development of novel epigenetic inhibitors as antitumor agents.

How Histone Acetyltransferases Shape Plant Photomorphogenesis and UV Response.

Higher plants have developed complex mechanisms to adapt to fluctuating environmental conditions with light playing a vital role in photosynthesis and influencing various developmental processes, including photomorphogenesis. Exposure to ultraviolet (UV) radiation can cause cellular damage, necessitating effective DNA repair mechanisms. Histone acetyltransferases (HATs) play a crucial role in regulating chromatin structure and gene expression, thereby contributing to the repair mechanisms. HATs facilitate chromatin relaxation, enabling transcriptional activation necessary for plant development and stress responses. The intricate relationship between HATs, light signaling pathways and chromatin dynamics has been increasingly understood, providing valuable insights into plant adaptability. This review explores the role of HATs in plant photomorphogenesis, chromatin remodeling and gene regulation, highlighting the importance of chromatin modifications in plant responses to light and various stressors. It emphasizes the need for further research on individual HAT family members and their interactions with other epigenetic factors. Advanced genomic approaches and genome-editing technologies offer promising avenues for enhancing crop resilience and productivity through targeted manipulation of HAT activities. Understanding these mechanisms is essential for developing strategies to improve plant growth and stress tolerance, contributing to sustainable agriculture in the face of a changing climate.

Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity.

BACKGROUND: Vascular smooth muscle cell (VSMC) phenotypic switching contributes to cardiovascular diseases. Epigenetic regulation is emerging as a key regulatory mechanism, with the methylcytosine dioxygenase TET2 acting as a master regulator of smooth muscle cell phenotype. The histone acetyl-transferases p300 and CREB-binding protein (CBP) are highly homologous and often considered to be interchangeable, and their roles in smooth muscle cell phenotypic regulation are not known. METHODS: We assessed the roles of p300 and CBP in human VSMC with knockdown, in inducible smooth muscle-specific knockout mice (inducible knockout [iKO]; p300iKO or CBPiKO), and in samples of human intimal hyperplasia. RESULTS: P300, CBP, and histone acetylation were differently regulated in VSMCs undergoing phenotypic switching and in vessel remodeling after vascular injury. Medial p300 expression and activity were repressed by injury, but CBP and histone acetylation were induced in neointima. Knockdown experiments revealed opposing effects of p300 and CBP in the VSMC phenotype: p300 promoted contractile protein expression and inhibited migration, but CBP inhibited contractile genes and enhanced migration. p300iKO mice exhibited severe intimal hyperplasia after arterial injury compared with controls, whereas CBPiKO mice were entirely protected. In normal aorta, p300iKO reduced, but CBPiKO enhanced, contractile protein expression and contractility compared with controls. Mechanistically, we found that these histone acetyl-transferases oppositely regulate histone acetylation, DNA hydroxymethylation, and PolII (RNA polymerase II) binding to promoters of differentiation-specific contractile genes. Our data indicate that p300 and TET2 function together, because p300 was required for TET2-dependent hydroxymethylation of contractile promoters, and TET2 was required for p300-dependent acetylation of these loci. TET2 coimmunoprecipitated with p300, and this interaction was enhanced by rapamycin but repressed by platelet-derived growth factor (PDGF) treatment, with p300 promoting TET2 protein stability. CBP did not associate with TET2, but instead facilitated recruitment of histone deacetylases (HDAC2, HDAC5) to contractile protein promoters. Furthermore, CBP inhibited TET2 mRNA levels. Immunostaining of cardiac allograft vasculopathy samples revealed that p300 expression is repressed but CBP is induced in human intimal hyperplasia. CONCLUSIONS: This work reveals that p300 and CBP serve nonredundant and opposing functions in VSMC phenotypic switching and coordinately regulate chromatin modifications through distinct functional interactions with TET2 or HDACs. Targeting specific histone acetyl-transferases may hold therapeutic promise for cardiovascular diseases.

Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis.

BACKGROUND: Epigenetic regulation relies on the activity of enzymes that use sentinel metabolites as cofactors to modify DNA or histone proteins. Thus, fluctuations in cellular metabolite levels have been reported to affect chromatin modifications. However, whether epigenetic modifiers also affect the levels of these metabolites and thereby impinge on downstream metabolic pathways remains largely unknown. Here, we tested this notion by investigating the function of N-alpha-acetyltransferase 40 (NAA40), the enzyme responsible for N-terminal acetylation of histones H2A and H4, which has been previously implicated with metabolic-associated conditions such as age-dependent hepatic steatosis and calorie-restriction-mediated longevity. RESULTS: Using metabolomic and lipidomic approaches, we found that depletion of NAA40 in murine hepatocytes leads to significant increase in intracellular acetyl-CoA levels, which associates with enhanced lipid synthesis demonstrated by upregulation in de novo lipogenesis genes as well as increased levels of diglycerides and triglycerides. Consistently, the increase in these lipid species coincide with the accumulation of cytoplasmic lipid droplets and impaired insulin signalling indicated by decreased glucose uptake. However, the effect of NAA40 on lipid droplet formation is independent of insulin. In addition, the induction in lipid synthesis is replicated in vivo in the Drosophila melanogaster larval fat body. Finally, supporting our results, we find a strong association of NAA40 expression with insulin sensitivity in obese patients. CONCLUSIONS: Overall, our findings demonstrate that NAA40 affects the levels of cellular acetyl-CoA, thereby impacting lipid synthesis and insulin signalling. This study reveals a novel path through which histone-modifying enzymes influence cellular metabolism with potential implications in metabolic disorders.

Garcinol and Anacardic Acid, Natural Inhibitors of Histone Acetyltransferases, Inhibit Rhabdomyosarcoma Growth and Proliferation.

Rhabdomyosarcoma (RMS) is a malignant tumour of the soft tissues. There are two main histopathological types: alveolar and embryonal. RMS occurs mainly in childhood and is a result of the deregulation of growth and differentiation of muscle cell precursors. There is an increasing amount of data indicating that numerous epigenetic alterations within chromatin and histone proteins are involved in the pathogenesis of this malignancy. Histone acetylation is one of the most important epigenetic modifications that is catalysed by enzymes from the group of histone acetyltransferases (HAT). In this study, the impact of the natural histone acetyltransferase inhibitors (HATi)-garcinol (GAR) and anacardic acid (AA)-on the biology of RMS cells was evaluated through a series of in vitro tests measuring proliferation, viability, clonogenicity, cell cycle and apoptosis. Moreover, using oligonucleotide microarrays and real-time PCR, we identified several genes whose expression changed after GAR and AA treatment. The examined HATi significantly reduce the invasive phenotype of RMS cells by inhibiting the growth rate, viability and clonogenic abilities. What is more, these substances cause cell cycle arrest in the G2/M phase, induce apoptosis and affect the genetic expression of the endoplasmic reticulum stress sensors. GAR and AA may serve as promising potential anti-cancer drugs since they sensitize the RMS cells to chemotherapeutic treatment.

A conserved acetylation switch enables pharmacological control of tubby-like protein stability.

Tubby-like proteins (TULPs) are characterized by a conserved C-terminal domain that binds phosphoinositides. Collectively, mammalian TULP1-4 proteins play essential roles in intracellular transport, cell differentiation, signaling, and motility. Yet, little is known about how the function of these proteins is regulated in cells. Here, we present the protein-protein interaction network of TULP3, a protein that is responsible for the trafficking of G-protein-coupled receptors to cilia and whose aberrant expression is associated with severe developmental disorders and polycystic kidney disease. We identify several protein interaction nodes linked to TULP3 that include enzymes involved in acetylation and ubiquitination. We show that acetylation of two key lysine residues on TULP3 by p300 increases TULP3 protein abundance and that deacetylation of these sites by HDAC1 decreases protein levels. Furthermore, we show that one of these sites is ubiquitinated in the absence of acetylation and that acetylation inversely correlates with ubiquitination of TULP3. This mechanism is evidently conserved across species and is active in zebrafish during development. Finally, we identify this same regulatory module in TULP1, TULP2, and TULP4 and demonstrate that the stability of these proteins is similarly modulated by an acetylation switch. This study unveils a signaling pathway that links nuclear enzymes to ciliary membrane receptors via TULP3, describes a dynamic mechanism for the regulation of all tubby-like proteins, and explores how to exploit it pharmacologically using drugs.

Histone acetylation dynamics regulating plant development and stress responses.

Crop productivity is directly dependent on the growth and development of plants and their adaptation during different environmental stresses. Histone acetylation is an epigenetic modification that regulates numerous genes essential for various biological processes, including development and stress responses. Here, we have mainly discussed the impact of histone acetylation dynamics on vegetative growth, flower development, fruit ripening, biotic and abiotic stress responses. Besides, we have also emphasized the information gaps which are obligatory to be examined for understanding the complete role of histone acetylation dynamics in plants. A comprehensive knowledge about the histone acetylation dynamics will ultimately help to improve stress resistance and reduce yield losses in different crops due to climate changes.

Acetylation-Specific Interference by Anti-Histone H3K9ac Intrabody Results in Precise Modulation of Gene Expression.

Among Histone post-translational modifications (PTMs), lysine acetylation plays a pivotal role in the epigenetic regulation of gene expression, mediated by chromatin modifying enzymes. Due to their activity in physiology and pathology, several chemical compounds have been developed to inhibit the function of these proteins. However, the pleiotropy of these classes of proteins represents a weakness of epigenetic drugs. Ideally, a new generation of epigenetic drugs should target with molecular precision individual acetylated lysines on the target protein. We exploit a PTM-directed interference, based on an intrabody (scFv-58F) that selectively binds acetylated lysine 9 of histone H3 (H3K9ac), to test the hypothesis that targeting H3K9ac yields more specific effects than inhibiting the corresponding HAT enzyme that installs that PTM. In yeast scFv-58F modulates, gene expression in a more specific way, compared to two well-established HAT inhibitors. This PTM-specific interference modulated expression of genes involved in ribosome biogenesis and function. In mammalian cells, the scFv-58F induces exclusive changes in the H3K9ac-dependent expression of specific genes. These results suggest the H3K9ac-specific intrabody as the founder of a new class of molecules to directly target histone PTMs, inverting the paradigm from inhibiting the writer enzyme to acting on the PTM.

Genome-wide identification of the histone acetyltransferase gene family in Triticum aestivum.

BACKGROUND: Histone acetylation is a ubiquitous and reversible post-translational modification in eukaryotes and prokaryotes that is co-regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC). HAT activity is important for the modification of chromatin structure in eukaryotic cells, affecting gene transcription and thereby playing a crucial regulatory role in plant development. Comprehensive analyses of HAT genes have been performed in Arabidopsis thaliana, Oryza sativa, barley, grapes, tomato, litchi and Zea mays, but comparable identification and analyses have not been conducted in wheat (Triticum aestivum). RESULTS: In this study, 31 TaHATs were identified and divided into six groups with conserved gene structures and motif compositions. Phylogenetic analysis was performed to predict functional similarities between Arabidopsis thaliana, Oryza sativa and Triticum aestivum HAT genes. The TaHATs appeared to be regulated by cis-acting elements such as LTR and TC-rich repeats. The qRT-PCR analysis showed that the TaHATs were differentially expressed in multiple tissues. The TaHATs in expression also responded to temperature changes, and were all significantly upregulated after being infected by barley streak mosaic virus (BSMV), Chinese wheat mosaic virus (CWMV) and wheat yellow mosaic virus (WYMV). CONCLUSIONS: These results suggest that TaHATs may have specific roles in the response to viral infection and provide a basis for further study of TaHAT functions in T. aestivum plant immunity.

Administration of branched-chain amino acids alters epigenetic regulatory enzymes in an animal model of Maple Syrup Urine Disease.

Maple Syrup Urine Disease (MSUD) is an autosomal recessive inherited disorder that affects the activity of the branched-chainα-keto acid dehydrogenase complex (BCDK). This deficiency on BCDK complex results in the accumulation of branched-chain amino acids (BCAA) leucine, isoleucine, valine, and their corresponding α-keto acids. Epigenetic changes can negatively affect the metabolism of BCAA. These changes are catalyzed by the epigenetic regulatory enzymes, e.g., DNA methyltransferase (DNMT), histone deacetylases (HDAC), and histone acetyltransferases (HAT). However, the impacts of BCAA administration on the activity of epigenetic regulatory enzymes in the brain of MSUD patients are still unknown. In this study, we aimed to demonstrate the impact of BCAA administration on the activity of DNMT, HDAC, and HAT in the brain structures of infant rats, an animal model of MSUD. For that, we administered a BCAA pool to infant rats for 21 days. We demonstrated that BCAA administration significantly increased the DNMT and HDAC activities in the hippocampus and striatum, but not in the cerebral cortex of MSUD infant rats. A positive correlation was observed between HDAC and DNMT activities in the hippocampus and striatum of animals exposed to BCAA injections. Our results showed that the BCAA administration could modulate epigenetic regulatory enzymes, mainly DNMT and HDAC, in the brains of infant rats. Therefore, we suggest that the increase in the activity of DNMT and HDAC in the hippocampus and striatum could partially explain the neurological impairments presented in animal models of MSUD.

Disruption in phosphate transport affects membrane lipid and lipid droplet homeostasis in Saccharomyces cerevisiae.

Phosphate plays a crucial role in phospholipid metabolism and it is transported by the phosphate (Pi) transporters. Phospholipids are building blocks of the cell membrane, and essential for cell growth; however, the role of phosphate transporters in lipid metabolism remains elusive. The present study shows that the deletion of Pi transporters exhibited an increase in both phospholipid and neutral lipid levels when compared to wild type. The mRNA expressions of genes involved in phospholipid synthesis (CKI1, EKI1, CHO2, and OPI3) were increased due to de-repression of the transcription factors (INO2 and INO4). Neutral lipid levels (triacylglycerol and sterol ester) and their synthesizing genes (LRO1, ARE2, ACC1, and FAS1) were also increased, resulting in lipid droplet accumulation in Pi transporter mutants. Interestingly, phospholipase (PLC1) and histone acetyltransferase genes (ESA1, EAF1, YNG1, YNG2, and GCN5) were also found to be significantly increased, leading to dysregulation of lipid levels in Pi transporter mutants. In summary, our results suggest that the Pi transporters are involved in lipid droplet and membrane lipid homeostasis.

Endocrine disrupting chemicals may deregulate DNA repair through estrogen receptor mediated seizing of CBP/p300 acetylase.

PURPOSE: Environmental pollutants are known to induce DNA breaks, leading to genomic instability. Here, we propose a novel mechanism for the genotoxic effects exerted by environmentally exposed endocrine-disrupting chemicals (EDCs). METHODS: Bibliographic research and presentation of the analysis. DISCUSSION: In mammals, nucleotide excision repair, base excision repair, homologous recombination and non-homologous end-joining pathways are some of the major DNA repair pathways. p300 along with CREB-binding protein (CBP) contributes to chromatin remodeling, DNA damage response and repair of both single- and double-stranded DNA breaks. In addition to its role in DNA repair, CBP/p300 also acts as a coactivator to interact with the estrogen receptor and androgen receptor during its estrogen- and androgen-dependent transactivation, respectively. Since activated estrogen receptors (ERs) seize p300 from the repressed genes and redistribute it to the enhancer genes to activate transcription, the cellular functioning may be based on a balance between these pathways and any disturbance in one may alter the other, leading to undesirable physiological effects. CONCLUSION: In conclusion, CBP/p300 is important for DNA repair and nuclear hormone receptor transactivation. Activated hormone receptors can sequester p300 to regulate the hormonal effects. Hence, we believe that activation of ERs by EDCs results in sequestration of CBP/p300 for ER transactivation and transcription initiation of its target genes, leading to a competition for CBP/P300, resulting in the deregulation of all other pathways involving p300/CBP.

A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets.

BACKGROUND & AIMS: A causal link has recently been established between epigenetic alterations and hepatocarcinogenesis, indicating that epigenetic inhibition may have therapeutic potential. We aimed to identify and target epigenetic modifiers that show molecular alterations in hepatocellular carcinoma (HCC). METHODS: We studied the molecular-clinical correlations of epigenetic modifiers including bromodomains, histone acetyltransferases, lysine methyltransferases and lysine demethylases in HCC using The Cancer Genome Atlas (TCGA) data of 365 patients with HCC. The therapeutic potential of epigenetic inhibitors was evaluated in vitro and in vivo. RNA sequencing analysis and its correlation with expression and clinical data in the TCGA dataset were used to identify expression programs normalized by Jumonji lysine demethylase (JmjC) inhibitors. RESULTS: Genetic alterations, aberrant expression, and correlation between tumor expression and poor patient prognosis of epigenetic enzymes are common events in HCC. Epigenetic inhibitors that target bromodomain (JQ-1), lysine methyltransferases (BIX-1294 and LLY-507) and JmjC lysine demethylases (JIB-04, GSK-J4 and SD-70) reduce HCC aggressiveness. The pan-JmjC inhibitor JIB-04 had a potent antitumor effect in tumor bearing mice. HCC cells treated with JmjC inhibitors showed overlapping changes in expression programs related with inhibition of cell proliferation and induction of cell death. JmjC inhibition reverses an aggressive HCC gene expression program that is also altered in patients with HCC. Several genes downregulated by JmjC inhibitors are highly expressed in tumor vs. non-tumor parenchyma, and their high expression correlates with a poor prognosis. We identified and validated a 4-gene expression prognostic signature consisting of CENPA, KIF20A, PLK1, and NCAPG. CONCLUSIONS: The epigenetic alterations identified in HCC can be used to predict prognosis and to define a subgroup of high-risk patients that would potentially benefit from JmjC inhibitor therapy. LAY SUMMARY: In this study, we found that mutations and changes in expression of epigenetic modifiers are common events in human hepatocellular carcinoma, leading to an aggressive gene expression program and poor clinical prognosis. The transcriptional program can be reversed by pharmacological inhibition of Jumonji enzymes. This inhibition blocks hepatocellular carcinoma progression, providing a novel potential therapeutic strategy.

Comparative Genome-wide Analysis and Expression Profiling of Histone Acetyltransferase (HAT) Gene Family in Response to Hormonal Applications, Metal and Abiotic Stresses in Cotton.

Post-translational modifications are involved in regulating diverse developmental processes. Histone acetyltransferases (HATs) play vital roles in the regulation of chromation structure and activate the gene transcription implicated in various cellular processes. However, HATs in cotton, as well as their regulation in response to developmental and environmental cues, remain unidentified. In this study, 9 HATs were identified from Gossypium raimondi and Gossypium arboretum, while 18 HATs were identified from Gossypium hirsutum. Based on their amino acid sequences, Gossypium HATs were divided into three groups: CPB, GNAT, and TAFII250. Almost all the HATs within each subgroup share similar gene structure and conserved motifs. Gossypium HATs are unevenly distributed on the chromosomes, and duplication analysis suggests that Gossypium HATs are under strong purifying selection. Gene expression analysis showed that Gossypium HATs were differentially expressed in various vegetative tissues and at different stages of fiber development. Furthermore, all the HATs were differentially regulated in response to various stresses (salt, drought, cold, heavy metal and DNA damage) and hormones (abscisic acid (ABA) and auxin (NAA)). Finally, co-localization of HAT genes with reported quantitative trait loci (QTL) of fiber development were reported. Altogether, these results highlight the functional diversification of HATs in cotton growth and fiber development, as well as in response to different environmental cues. This study enhances our understanding of function of histone acetylation in cotton growth, fiber development, and stress adaptation, which will eventually lead to the long-term improvement of stress tolerance and fiber quality in cotton.

Epigenetic regulation of integrin ß6 transcription induced by TGF-ß1 in human oral squamous cell carcinoma cells.

Overexpression of integrin αvß6 is believed to play an important role in the invasion and metastasis of oral squamous cell carcinoma (OSCC). However, little is known about the molecular mechanisms leading to αvß6 upregulation in OSCC. As the integrin ß6 (ITGB6) is the only partner with αv, the expression of αvß6 is dependent on ITGB6, it is, therefore, pivotal to investigate the mechanisms underlying ITGB6 overexpression in OSCC. We previously reported the cloning and characterization of human ITGB6 gene. In the current study, we further investigated the molecular mechanisms of ITGB6 expression and the upregulation by carcinogenesis related cytokine-transforming growth factor-ß1 (TGF-ß1) in OSCC cells. We first demonstrated that TGF-ß1 can induce ITGB6 mRNA and protein express in a time and concentration dependent manner, and the induced-ITGB6 mRNA was not due to increase the mRNA stability, but regulated at transcriptional level. By using a luciferase reporter assay, site-mutation, RNA interference, and chromatin immunoprecipitation assay, we revealed for the first time that JunB, a member of the activator protein-1 (AP-1) family, is involved in the positive regulation to the ITGB6 transcription induced by TGF-ß1 in OSCC cells. Furthermore, our data also demonstrated that histone acetyltransferase (HAT) CBP mediated histone H3 and H4 hyperacetylation, and RNA Polymerase II recruitment to ITGB6 promoter, facilitated the binding of transcription factor JunB to ITGB6 promoter after TGF-ß1 stimulation. Collectively, these findings demonstrate that JunB and CBP-mediated histone hyperacetylation are responsible for TGF-ß1 induced ITGB6 transcription in OSCC cells, suggesting that epigenetic mechanisms are responsible for the active transcription expression of ITGB6 induced by TGF-ß1 in OSCC cells.

K-Lysine acetyltransferase 2a regulates a hippocampal gene expression network linked to memory formation.

Neuronal histone acetylation has been linked to memory consolidation, and targeting histone acetylation has emerged as a promising therapeutic strategy for neuropsychiatric diseases. However, the role of histone-modifying enzymes in the adult brain is still far from being understood. Here we use RNA sequencing to screen the levels of all known histone acetyltransferases (HATs) in the hippocampal CA1 region and find that K-acetyltransferase 2a (Kat2a)--a HAT that has not been studied for its role in memory function so far--shows highest expression. Mice that lack Kat2a show impaired hippocampal synaptic plasticity and long-term memory consolidation. We furthermore show that Kat2a regulates a highly interconnected hippocampal gene expression network linked to neuroactive receptor signaling via a mechanism that involves nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In conclusion, our data establish Kat2a as a novel and essential regulator of hippocampal memory consolidation.