Genome-wide identifcation of the histone acetyltransferase gene family in Citrus clementina and its potential roles in citrate metabolism

Histone acetyltransferase(HAT)catalyzes histone acetylation and is involved in plant growth and development and stress responses.Here,37 CitHAT genes were identifed in Citrus clementina.Their physicochemical properties,chromosomal location,gene structure,conserved domain and motif,and cis-acting elements were characterized.CitHATs were classifed into four subfamilies based on protein sequence homology,which was strongly supported by gene structure,conserved domain,and motif analysis.The cis-acting elements in gene promoter regions were predicted to be associated with the regulation of plant growth,stress resistance,and response to hormones.Phenotypic and transcriptomic analyses of citrus callus with mock treatment and HAT inhibitor treatment revealed that increased citric acid content in inhibitor treatment may be attributed to differential expression of CitPEPCK2 and CitGS2,which may be due to the hypo-acetylation of histone H3.The expression patterns of CitHATs in citrus fruit development stages showed that CitHAG11 and CitHAG28 exhibited a negative correlation with citric acid content.Our study associates the potential function of histone acetyltransferases in citrate metabolism and extends the molecular mechanism of citrate metabolism in fruits.

The Arabidopsis NuA4 histone acetyltransferase complex is required for chlorophyll biosynthesis and photosynthesis

Although two Enhancer of Polycomb-like proteins,EPL1 A and EPL1 B(EPL1 A/B),are known to be conserved and characteristic subunits of the Nu A4-type histone acetyltransferase complex in Arabidopsis thaliana,the biological function of EPL1 A/B and the mechanism by which EPL1 A/B function in the complex remain unknown.Here,we report that EPL1 A/B are required for the histone acetyltransferase activity of the Nu A4 complex on the nucleosomal histone H4 in vitro and for the enrichment of histone H4 K5 acetylation at thousands of protein-coding genes in vivo.Our results suggest that EPL1 A/B are required for linking the Nu A4 catalytic subunits HISTONE ACETYLTRANSFERASE OF THE MYST FAMILY 1(HAM1)and HAM2 with accessory subunits in the Nu A4 complex.EPL1 A/B function redundantly in regulating plant development especially in chlorophyll biosynthesis and de-etiolation.The EPL1 A/B-dependent transcription and H4 K5 Ac are enriched at genes involved in chlorophyll biosynthesis and photosynthesis.We also find that EAF6,another characteristic subunit of the Nu A4 complex,contributes to de-etiolation.These results suggest that the Arabidopsis Nu A4 complex components function as a whole to mediate histone acetylation and transcriptional activation specifically at light-responsive genes and are critical for photomorphogenesis.

Regulation and function of histone acetyltransferase MOF

The mammalian MOF （male absent on the first）, a member of the MYST （MOZ, YBF2, SAS2, and Tip60） family of histone acetyltransferases （HATs）, is the major enzyme that catalyzes the acetylation of histone H4 on lysine 16. Acetylation of K16 is a prevalent mark associated with chromatin decondensation. MOF has recently been shown to play an essential role in maintaining normal cell functions. In this study, we discuss the important roles of MOF in DNA damage repair, apoptosis, and tumorigenesis. We also analyze the role of MOF as a key regulator of the core transcriptional network of embryonic stem cells.

The histone acetyltransferase MOF is required for the cellular stress response

When exposing to environmental stress or internal damage,such as genotoxic stress,oxidative stress,and heat stress,cells produce a series of adaptive responses called cellular stress responses[1].The major proteins involved in cellular stress are heat shock proteins(HSPs).HSPs remain in a low expression level and display a diffused distribution in the nucleoplasm and cytoplasm under basal conditions.In response to various stress conditions。

ENHANCED EXPRESSION OF hALP GENE CONFERS CELLULAR RESISTANCE TO H_2O_2 INDUCED SENESCENCE

Objective To investigate the H_ 2O_ 2-induced expression of human histone acetyltransferase-like protein (hALP), a telomerase regulation-associated gene, and its effects on the stress-triggered cellular senescence.Methods The induced expression of hALP was measured by semi-quantitative RT-PCR and immunofluorescent histochemistry after treatment of HeLa cells by H_ 2O_ 2.The effects of hALP expression on cellular responses to H_ 2O_ 2 were analyzed by MTT, flowcytometry, and SA-β-gal staining, respectively.Results hALP mRNA could be dose-dependently induced by treatments of 0.2-1.6 mmol/L H_ 2O_ 2, and the induction could be observed after 6 hours and kept for 36 hours in the presence of 0.4 mmol/L H_ 2O_ 2.Meanwhile, the immunofluorescent staining showed marked stronger nuclear intensity of hALP protein in H_ 2O_ 2-treated HeLa cells.In the treatment of H_ 2O_ 2, the ectopic expression of hALP enhanced continuous growth and overcame G_ 2/M arrest as well as decreased senescence-associated β-gal staining.On the contrary, the transfected clones with antisense or blank vector and original HeLa cells presented growth suppression, G_ 2/M delay and higher percentage of SA-β-gal activities in the presence of H_ 2 O_ 2.Conclusions The expression of hALP could be up-regulated by treatment of H_ 2O_ 2, and elevated expression could enhance cellular resistance to H_ 2O_ 2-induced cellular senescence.The data might be of references to elucidation of basic biological function of hALP gene and its associated telomerase activity.

The Epigenome as a therapeutic target for Parkinson's disease

Parkinson＇s disease （PD） is a common, progressive neurodegenerative disease characterised by degeneration of nigrostriatal dopaminergic neurons, aggregation of α-synuclein and motor symptoms. Current dopamine-replacement strategies provide symptomatic relief, however their effectiveness wear off over time and their prolonged use leads to disabling side-effects in PD patients. There is therefore a critical need to develop new drugs and drug targets to protect dopaminergic neurons and their axons from degeneration in PD. Over recent years, there has been robust evidence generated showing that epigenetic dysregulation occurs in PD patients, and that epigenetic modulation is a promising therapeutic approach for PD. This ar- ticle first discusses the present evidence implicating global, and dopaminergic neuron-specific, akerations in the methylome in PD, and the therapeutic potential of pharmacologically targeting the methylome. It then focuses on another mechanism of epigenetic regulation, histone acetylation, and describes how the histone acetyltransferase （HAT） and histone deacetylase （HDAC） enzymes that mediate this process are attractive therapeutic targets for PD. It discusses the use of activators and/or inhibitors of HDACs and HATs in models of PD, and how these approaches for the selective modulation of histone acetylation elicit neuroprotective effects. Finally, it outlines the potential of employing small molecule epigenetic modulators as neuroprotective therapies for PD, and the future research that will be required to determine and realise this therapeutic potential.

Histone Acetylation, VERNALIZATION INSENSITIVE 3, FLOWERING LOCUS C, and the Vernalization Response

The quantitative induction of VIN3 by low temperatures is required for PRC2 repression of FLC and promotion of flowering （vernalization） in Arabidopsis. Histone acetylation, a chromatin modification commonly associated with gene transcription, increased on VIN3 chromatin in two spatially and temporally distinct phases in response to low temperatures. During short-term cold exposure, histone H3 acetylation at the transcription start site rapidly increased, implying that it is required for VlN3 induction. Subsequent changes in histone H3 and H4 acetylation occurred following continued VIN3 transcription during prolonged cold exposure. Members of the SAGA-like transcriptional adaptor complex, including the histone acetyltransferase GCNS, which induces expression of the cold acclimation pathway genes, do not regulate VlN3 induction during cold exposure, indicating that the cold acclimation pathway and the cold-induction of VlN3 are regulated by different transcriptional mechanisms. Mutations in the other 11 histone acetyltransferase genes did not affect VlN3 induction. However, nicotinamide, a histone deacetyiase inhibitor, induced VIN3 and altered histone acetylation at the VIN3 locus. VIN3 induction was proportional to the length of nicotinamide treatment, which was associated with an early-flowering phenotype and repression of FLC. However, unlike vernalization, the repression of FLC was independent of VIN3 activity. Nicotinamide treatment did not cause a change in the expression of any genes in the autonomous pathway or members of the PRC2 complex, the well characterized repressors of FLC. Our data suggest that FLC is repressed via a novel pathway involving the SIR2 class of histone deacetylases.

Histone deacetylases and their inhibitors:molecular mechanisms and therapeutic implications in diabetes mellitus

Epigenetic mechanisms such as DNA methylation,histone modification and microRNA changes have been shown to be important for the regulation of cellular functions.Among them,histone deacetylases(HDACs)are enzymes that balance the acetylation activities of histone acetyltransferases in chromatin remodeling and play essential roles in gene transcription to regulate cell proliferation,migration and death.Recent studies indicate that HDACs are promising drug targets for a wide range of diseases including cancer,neurodegenerative and psychiatric disorders,cardiovascular dysfunction,autoimmunity and diabetes mellitus.This review highlights the role of HDACs in diabetes mellitus and outlines several important cellular and molecular mechanisms by which HDACs regulate glucose homeostasis and can be targeted for the treatment of dia betic microvascular complications.It is hoped that our understanding of the role of HDACs in diabetes.mellitus will lead to the development of better diagnostic tools and the design of more potent and specific drugs targeting selective HDAC proteins for the treatment of the disease.

Enriched gestation activates the IGF pathway to evoke embryo-adult benefits to prevent Alzheimer’s disease

Background:Building brain reserves before dementia onset could represent a promising strategy to prevent Alzheimer’s disease(AD),while how to initiate early cognitive stimulation is unclear.Given that the immature brain is more sensitive to environmental stimuli and that brain dynamics decrease with ageing,we reasoned that it would be effective to initiate cognitive stimulation against AD as early as the fetal period.Methods:After conception,maternal AD transgenic mice(3×Tg AD)were exposed to gestational environment enrichment(GEE)until the day of delivery.The cognitive capacity of the offspring was assessed by the Morris water maze and contextual fear-conditioning tests when the offspring were raised in a standard environment to 7 months of age.Western blotting,immunohistochemistry,real-time PCR,immunoprecipitation,chromatin immunoprecipitation(ChIP)assay,electrophysiology,Golgi staining,activity assays and sandwich ELISA were employed to gain insight into the mechanisms underlying the beneficial effects of GEE on embryos and 7–10-month-old adult offspring.Results:We found that GEE markedly preserved synaptic plasticity and memory capacity with amelioration of hallmark pathologies in 7–10-m-old AD offspring.The beneficial effects of GEE were accompanied by global histone hyperacetylation,including those at bdnf promoter-binding regions,with robust BDNF mRNA and protein expression in both embryo and progeny hippocampus.GEE increased insulin-like growth factor 1(IGF1)and activated its receptor(IGF1R),which phosphorylates Ca^(2+)/calmodulin-dependent kinase IV(CaMKIV)at tyrosine sites and triggers its nuclear translocation,subsequently upregulating histone acetyltransferase(HAT)and BDNF transcription.The upregulation of IGF1 mimicked the effects of GEE,while IGF1R or HAT inhibition during pregnancy abolished the GEE-induced CaMKIV-dependent histone hyperacetylation and BDNF upregulation.Conclusions:These findings suggest that activation of IGF1R/CaMKIV/HAT/BDNF signaling by gestational environment enrichment may serve as a promising strategy to delay AD progression.