Sodium butyrate alleviates deoxynivalenol-induced hepatic cholesterol metabolic dysfunction via RORγ-mediated histone acetylation modification in weaning piglets

Background:Cholesterol is an essential component of lipid rafts in cell plasma membrane,which exerts a hepatoprotective role against mycotoxin exposure in pigs,and cholesterol metabolism is vulnerable to epigenetic histone acetylation.Therefore,our present study aimed to investigate whether a histone deacetylase inhibitor(sodium butyrate [NaBu]) could protect the porcine liver from deoxynivalenol(DON) exposure by modulating cholesterol metabolism.Herein,we randomly divided 28 pigs into four groups,which were fed an uncontaminated basal diet,contaminated diet(4 mg DON/kg),uncontaminated diet supplemented with 0.2% NaBu or 4 mg/kg DON contaminated diet(4 mg DON/kg) supplemented with 0.2% NaBu for 28 d.Results:We found that the serum alanine transaminase(ALT),aspartate transaminase(AST),and alkaline phosphatase(ALP) were all increased in pigs exposed to DON,indicative of significant liver injury.Furthermore,the cholesterol content in the serum of DON-exposed pigs was significantly reduced,compared to the healthy Vehicle group.Transcriptome analysis of porcine liver tissues revealed that the cholesterol homeostasis pathway was highly enriched due to DON exposure.In which we validated by qRT-PCR and western blotting that the cholesterol program was markedly activated.Importantly,NaBu effectively restored parameters associated with liver injury,along with the cholesterol content and the expression of key genes involved in the cholesterol biosynthesis pathway.Mechanistically,we performed a ChIP-seq analysis of H3K27ac and showed that NaBu strongly diminished DON-increased H3K27ac genome-wide enrichment.We further validated that the elevated H3K27ac and H3K9ac occupancies on cholesterol biosynthesis genes were both decreased by NaBu,as determined by ChIP-qPCR analysis.Notably,nuclear receptor RORγ,a novel regulator of cholesterol biosynthesis,was found in the hyperacetylated regions.Again,a remarkable increase of RORγ at both mRNA and protein levels in DON-exposed porcine livers was drastically reduced by NaBu.Consistent with RORγ expression,NaBu also hindered RORγ transcriptional binding enrichments on these activated cholesterol biosynthesis genes like HMGCR,SQLE,and DHCR24.Furthermore,we conducted an in vitro luciferase reporter assay to verify that porcine RORγ directly bonds to the promoters of the above target genes.Conclusions:Collectively,our results demonstrate the utility of the natural product Na Bu as a potential anti-mycotoxin nutritional strategy for regulating cholesterol metabolism via RORγ-mediated histone acetylation modification.

Effects of Triptolide on Histone Acetylation and HDAC8 Expression in Multiple Myeloma in vitro

客观多重骨髓瘤是从 B 淋巴细胞发源的一种恶意的血浆房间疾病并且分泌 monoclonal 免疫球蛋白的大数量。它仍然目前是倔强的疾病之一。众多的研究证明在 histone acetylation 的不平衡和多重骨髓瘤的 occurance 之间有一种集中的关系。这里，我们在增长， apoptosis， histone H3 和 H4 acetylation 和 histone deacetylase 的表示上调查了 triptolide (TPL ) 的效果 8 (HDAC8 ) 在 vitro，探索它的反骨髓瘤机制。RPMI8226 的生长上的 triptolide 的效果被 3-(4,5-Dimethyl-2-thiazolyl ) 学习的方法 -2,5-diphenyl-2H-tetrazolium(MTT) 试金。Apoptosis 被染色的 Hoechst 33258 检测。acetyl-histone H3 和 H4 的蛋白质表情被西方的污点决定，并且 HDAC8 的表示被 RT-PCR，西方的污点和共焦的显微镜学估计。结果 Triptolide 禁止了 RPMI8226 的增长并且在一个时间依赖者和剂量依赖者举止导致了 apoptosis。36h IC50 价值是(105.370 敢漠 ? 摀畲獧吗？

Reducing histone acetylation rescues cognitive deficits in mouse model of fragile X syndrome

Fragile X syndrome(FXS)is the most prevalent inherited intellectual disability,resulting from a loss of fragile X mental retardation protein(FMRP).Patients with FXS suffer lifelong cognitive disabilities,but the function of FMRP in the adult brain and the mechanism underlying age-related cognitive decline in FXS is not fully understood.Here,we report that a loss of FMRP results in increased protein synthesis of histone acetyltransferase EP300 and ubiquitinationmediated degradation of histone deacetylase HDAC1 in adult hippocampal neural stem cells(NSCs).Consequently,FMRPdeficient NSCs exhibit elevated histone acetylation and age-related NSC depletion,leading to cognitive impairment in mature adult mice.Reducing histone acetylation rescues both neurogenesis and cognitive deficits in mature adult FMRPdeficient mice.Our work reveals a role for FMRP and histone acetylation in cognition and presents a potential novel ther⁃apeutic strategy for treating adult FXS patients.

Dynamic profiles of DNA methylation and the interaction with histone acetylation during fiber cell initiation of Gossypium hirsutum

Background:Fiber,as the main product of cotton,provides main raw material for the textile industry.Many key factors have been revealed a significant role in fiber cell development including Myb proteins,phytohormones,fatty acid metabolites,and epigenetic modifications.DNA methylation is one of the important epigenetic modifications to regulate plant development and responses to abiotic or biotic stimuli.In general,DNA methylation consisting of 5mC and 6mA regulates the chromatin structure and gene transcription to affect plant development,however,the detailed role and underlying mechanism of DNA methylation in the fiber development of cotton are yet vague.Results:Here,systematical study of the 5mC and 6mA DNA methylation profiles during the fiber initiation period of Xu142 and its glabrous mutant Xu142fl represented a clear alteration of global DNA methylation associated with fiber cell initiation.Then,the genome-wide identification of genes responsible for methylation regulation at the fifth carbon of cytosine and the sixth carbon of adenine of DNA was operated in Gossypium hirsutum.As a result,13,10,6,and 17 genes were identified for 5mC methylation,5mC demethylation,6mA methylation,and 6mA demethylation,respectively.We then investigated the tissue expression pattern of all these genes,and some genes showed higher expression levels in fiber initiation,among which some displayed a significant change in transcription between Xu142 and Xu142fl.The possible interaction between histone acetylation and DNA methylation in fiber initiation through in vitro culture was studied by dot blot,and the results showed that repressed histone deacetylation by Trichostatin A(TSA)inhibited the global DNA methylation,and some causal genes(e.g.,GhDMT13,GhDAMT2,GhALKBH12,GhDM7)were also identified.Conclusions:In this study,all the findings indicated the interplay between histone acetylation and DNA methylation,supporting their important roles and providing precious clues for the epigenetic modifications associated with DNA methylation in the fiber development of cotton.

The secondary laticifer differentiation in rubber tree is induced by trichostatin A, an inhibitor of histone acetylation

The secondary laticifer, a specific tissue in the secondary phloem of rubber tree, is differentiated from the vascular cambia. The number of the secondary laticifer in the trunk bark of rubber tree is positively correlated with rubber yield. Although jasmonates have been demonstrated to be crucial in the regulation of secondary laticifer differentiation, the mechanism for the jasmonate-induced secondary laticifer differentiation remains to be elucidated.By using an experimental morphological technique, the present study revealed that trichostatin A(TSA), an inhibitor of histone deacetylation, could induce the secondary laticifer differentiation in a concentrationdependent manner. The results suggest that histone acetylation is essential for the secondary laticifer differentiation in rubber tree.

Histone deacetylase inhibitor pre-treatment enhances the efficacy of DNA-interacting chemotherapeutic drugs in gastric cancer

BACKGROUND The prognosis of gastric cancer continues to remain poor,and epigenetic drugs like histone deacetylase inhibitors(HDACi)have been envisaged as potential therapeutic agents.Nevertheless,clinical trials are facing issues with toxicity and efficacy against solid tumors,which may be partly due to the lack of patient stratification for effective treatments.To study the need of patient stratification before HDACi treatment,and the efficacy of pre-treatment of HDACi as a chemotherapeutic drug sensitizer.METHODS The expression activity of class 1 HDACs and histone acetylation was examined in human gastric cancer cells and tissues.The potential combinatorial regime of HDACi and chemotherapy drugs was defined on the basis of observed drug binding assays,chromatin remodeling and cell death.RESULTS In the present study,the data suggest that the differential increase in HDAC activity and the expression of class 1 HDACs are associated with hypoacetylation of histone proteins in tumors compared to normal adjacent mucosa tissue samples of gastric cancer.The data highlights for the first time that pretreatment of HDACi results in an increased amount of DNA-bound drugs associated with enhanced histone acetylation,chromatin relaxation and cell cycle arrest.Fraction-affected plots and combination index-based analysis show that pre-HDACi chemo drug combinatorial regimes,including valproic acid with cisplatin or oxaliplatin and trichostatin A with epirubicin,exhibit synergism with maximum cytotoxic potential due to higher cell death at low combined doses in gastric cancer cell lines.CONCLUSION Expression or activity of class 1 HDACs among gastric cancer patients present an effective approach for patient stratification.Furthermore,HDACi therapy in pretreatment regimes is more effective with chemotherapy drugs,and may aid in predicting individual patient prognosis.

Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases

The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses,thus allowing continuous tumor growth and development.Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer.Compared with other cancers,pancreatic cancer has a tumor microenvironment that can resist most treatment modalities,including emerging immunotherapy.Sadly,the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients,suggesting that pancreatic cancer has successfully evaded immunomodulation.In this review,we summarize the impact of genetic alteration and epigenetic modification(especially histone deacetylases,HDAC)on immune evasion in pancreatic cancer.HDAC overexpression significantly suppresses tumor suppressor genes,contributing to tumor growth and progression.We review the evidence on HDAC inhibitors in tumor eradication,improving T cells activation,restoring tumor immunogenicity,and modulating programmed death 1 interaction.We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.

Butyrate stimulates IL-32α expression in human intestinal epithelial cell lines

AIM: To investigate the effects of butyrate on interleukin (IL)-32α expression in epithelial cell lines. METHODS: The human intestinal epithelial cell lines HT-29, SW480, and T84 were used. Intracellular IL- 32α was determined by Western blotting analyses. IL- 32α mRNA expression was analyzed by real-time poly-merase chain reaction. RESULTS: Acetate and propionate had no effects on IL-32α mRNA expression. Butyrate significantly enhanced IL-32α expression in all cell lines. Butyrate also up-regulated IL-1β-induced IL-32α mRNA expression. Butyrate did not modulate the activation of phosphatidylinositol 3-kinase (PI3K), a mediator of IL- 32α expression. Like butyrate, trichostatin A, a histone deacetylase inhibitor, also enhanced IL-1β-induced IL- 32α mRNA expression.CONCLUSION: Butyrate stimulated IL-32α expression in epithelial cell lines. An epigenetic mechanism, such as histone hyperacetylation, might be involved in the action of butyrate on IL-32α expression.

Neuroendocrine,epigenetic,and intergenerational effects of general anesthetics

The progress of modern medicine would be impossible without the use of general anesthetics(GAs).Despite advancements in refining anesthesia approaches,the effects of GAs are not fully reversible upon GA withdrawal.Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly.Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research,but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects.The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents,which are far more extensively studied than any other species.Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated.Specifically,we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities(somatic effects),but also epigenetic reprogramming of germ cells(germ cell effects).The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring,who may be affected even at levels of anesthesia that are not harmful to the exposed parents.The large number of patients who require general anesthesia,the even larger number of their future unexposed offspring whose health may be affected,and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs.In this mini review,we discuss emerging experimental findings on neuroendocrine,epigenetic,and intergenerational effects of GAs.

Hedgehog pathway orchestrates the interplay of histone modifications and tailors combination epigenetic therapies in breast cancer

Epigenetic therapies that cause genome-wide epigenetic alterations,could trigger local interplay between different histone marks,leading to a switch of transcriptional outcome and therapeutic responses of epigenetic treatment.However,in human cancers with diverse oncogenic activation,how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood.We herein discover that the hedgehog(Hh)pathway reprograms the histone methylation landscape in breast cancer,especially in triple-negative breast cancer(TNBC).This facilitates the histone acetylation caused by histone deacetylase(HDAC)inhibitors and gives rise to new therapeutic vulnerability of combination therapies.Specifically,overexpression of zinc finger protein of the cerebellum 1(ZIC1)in breast cancer promotes Hh activation,facilitating the switch of H3K27 methylation(H3K27me)to acetylation(H3K27ac).The mutually exclusive relationship of H3K27me and H3K27ac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes.Using multiple in vivo breast cancer models including patient-derived TNBC xenograft,we show that Hh signaling-orchestrated H3K27me and H3K27ac interplay tailors combination epigenetic drugs in treating breast cancer.Together,this study reveals the new role of Hh signaling-regulated histone modifications interplay in responding to HDAC inhibitors and suggests new epigenetically-targeted therapeutic solutions for treating TNBC.

OsWR2 recruits HDA704 to regulate the deacetylation of H4K8ac in the promoter of OsABI5 in response to drought stress

Drought stress is a major environmental factor that limits the growth, development, and yield of rice(Oryza sativa L.). Histone deacetylases(HDACs) are involved in the regulation of drought stress responses. HDA704 is an RPD3/HDA1 class HDAC that mediates the deacetylation of H4K8(lysine 8of histone H4) for drought tolerance in rice. In this study, we show that plants overexpressing HDA704(HDA704-OE) are resistant to drought stress and sensitive to abscisic acid(ABA), whereas HDA704 knockout mutant(hda704) plants displayed decreased drought tolerance and ABA sensitivity.Transcriptome analysis revealed that HDA704 regulates the expression of ABA-related genes in response to drought stress. Moreover, HDA704 was recruited by a drought-resistant transcription factor,WAX SYNTHESIS REGULATORY 2(Os WR2), and co-regulated the expression of the ABA biosynthesis genes NINE-CIS-EPOXYCAROTENOID DIOXYGENASE 3(NCED3), NCED4, and NCED5 under drought stress. HDA704 also repressed the expression of ABA-INSENSITIVE 5(Os ABI5) and DWARF AND SMALL SEED 1(Os DSS1) by regulating H4K8ac levels in the promoter regions in response to polyethylene glycol 6000 treatment. In agreement, the loss of Os ABI5 function increased resistance to dehydration stress in rice. Our results demonstrate that HDA704 is a positive regulator of the drought stress response and offers avenues for improving drought resistance in rice.

A domesticated Harbinger transposase forms a complex with HDA6 and promotes histone H3 deacetylation at genes but not TEs in Arabidopsis

In eukaryotes,histone acetylation is a major modification on histone N-terminal tails that is tightly connected to transcriptional activation.HDA6 is a histone deacetylase involved in the transcriptional regulation of genes and transposable elements(TEs)in Arabidopsis thaliana.HDA6 has been shown to participate in several complexes in plants,including a conserved SIN3 complex.Here,we uncover a novel protein complex containing HDA6,several Harbinger transposon-derived proteins(HHP1,SANT1,SANT2,SANT3,and SANT4),and MBD domain-containing proteins(MBD1,MBD2,and MBD4).We show that mutations of all four SANT genes in the sant-null mutant cause increased expression of the flowering repressors FLC,MAF4,and MAF5,resulting in a late flowering phenotype.Transcriptome deep sequencing reveals that while the SANT proteins and HDA6 regulate the expression of largely overlapping sets of genes,TE silencing is unaffected in sant-null mutants.Our global histone H3 acetylation profiling shows that SANT proteins and HDA6 modulate gene expression through deacetylation.Collectively,our findings suggest that Harbinger transposon-derived SANT domain-containing proteins are required for histone deacetylation and flowering time control in plants.

Single-cell RNA sequencing of mitoticarrested prospermatogonia with DAZL::GFP chickens and revealing unique epigenetic reprogramming of chickens

Background:Germ cell mitotic arrest is conserved in many vertebrates,including birds,although the time of entry or exit into quiescence phase differs.Mitotic arrest is essential for the normal differentiation of male germ cells into spermatogonia and accompanies epigenetic reprogramming and meiosis inhibition from embryonic development to post-hatch.However,mitotic arrest was not well studied in chickens because of the difficulty in obtaining pure germ cells from relevant developmental stage.Results:We performed single-cell RNA sequencing to investigate transcriptional dynamics of male germ cells during mitotic arrest in DAZL::GFP chickens.Using differentially expressed gene analysis and K-means clustering to analyze cells at different developmental stages(E12,E16,and hatch),we found that metabolic and signaling pathways were regulated,and that the epigenome was reprogrammed during mitotic arrest.In particular,we found that histone H3K9 and H3K14 acetylation(by HDAC2)and DNA demethylation(by DNMT3B and HELLS)led to a transcriptionally permissive chromatin state.Furthermore,we found that global DNA demethylation occurred gradually after the onset of mitotic arrest,indicating that the epigenetic-reprogramming schedule of the chicken genome differs from that of the mammalian genome.DNA hypomethylation persisted after hatching,and methylation was slowly re-established 3 weeks later.Conclusions:We found a unique epigenetic-reprogramming schedule of mitotic-arrested chicken prospermatogonia and prolonged hypomethylation after hatching.This will provide a foundation for understanding the process of germ-cell epigenetic regulation in several species for which this process is not clearly described.Our findings on the biological processes related to sex-specific differentiation of prospermatogonia could help studying germline development in vitro more elaborately.

Epigenetic regulation of mesenchymal stem cell aging through histone modifications

Stem cell senescence and exhaustion,a hallmark of aging,lead to declines in tissue repair and regeneration in aged individuals.Emerging evidence has revealed that epigenetic regulation plays critical roles in the self-renew,lineage-commitment,survival,and function of stem cells.Moreover,epigenetic alterations are considered important drivers of stem cell dysfunction during aging.In this review,we focused on current knowledge of the histone modifications in the aging of mesenchymal stem cells(MSCs).The aberrant epigenetic modifications on histones,including methylation and acetylation,have been found in aging MSCs.By disturbing the expression of specific genes,these epigenetic modifications affect the self-renew,survival,and differentiation of MSCs.A set of epigenetic enzymes that write or erase these modifications are critical in regulating the aging of MSCs.Furthermore,we discussed the rejuvenation strategies based on epigenetics to prevent stem cell aging and/or rejuvenate senescent MSCs.

AIMP1 promotes multiple myeloma malignancy through interacting with ANP32A to mediate histone H3 acetylation

Background:Multiple myeloma(MM)is the second most common hematological malignancy.An overwhelming majority of patients with MM progress to serious osteolytic bone disease.Aminoacyl-tRNA synthetase-interacting multifunctional protein 1(AIMP1)participates in several steps during cancer development and osteoclast differentiation.This study aimed to explore its role in MM.Methods:The gene expression profiling cohorts of MM were applied to determine the expression of AIMP1 and its association with MM patient prognosis.Enzyme-linked immunosorbent assay,immunohistochemistry,and Western blotting were used to detect AIMP1 expression.Protein chip analysis,RNA-sequencing,and chromatin immunoprecipitation and next-generation sequencing were employed to screen the interacting proteins and key downstream targets of AIMP1.The impact of AIMP1 on cellular proliferation was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay in vitro and a xenograft model in vivo.Bone lesions were evaluated using tartrate-resistant acid phosphatase staining in vitro.A NOD/SCID-TIBIA mouse model was used to evaluate the effect of siAIMP1-loaded exosomes on bone lesion formation in vivo.Results:AIMP1 expression was increased in MM patients and strongly associated with unfavorable outcomes.Increased AIMP1 expression promoted MM cell proliferation in vitro and in vivo via activation of the mitogen-activated protein kinase(MAPK)signaling pathway.Protein chip assays and subsequent experiments revealed that AIMP1 interacted with acidic leucine-rich nuclear phosphoprotein 32 family member A(ANP32A)to regulate histone H3 acetylation.In addition,AIMP1 increased histone H3 acetylation enrichment function of GRB2-associated and regulator of MAPK protein 2(GAREM2)to increase the phosphorylation of extracellular-regulated kinase 1/2(p-ERK1/2).Furthermore,AIMP1 promoted osteoclast differentiation by activating nuclear factor of activated T cells c1(NFATc1)in vitro.In contrast,exosome-coated small interfering RNA of AIMP1 effectively suppressed MM progression and osteoclast differentiation in vitro and in vivo.Conclusions:Our data demonstrate that AIMP1 is a novel regulator of histone H3 acetylation interacting with ANP32A in MM,which accelerates MM malignancy via activation of the MAPK signaling pathway.

Epigenetic modification in liver fibrosis:Promising therapeutic direction with significant challenges ahead

Liver fibrosis,characterized by scar tissue formation,can ultimately result in liver failure.It’s a major cause of morbidity and mortality globally,often associated with chronic liver diseases like hepatitis or alcoholic and non-alcoholic fatty liver diseases.However,current treatment options are limited,highlighting the urgent need for the development of new therapies.As a reversible regulatory mechanism,epigenetic modification is implicated in many biological processes,including liver fibrosis.Exploring the epigenetic mechanisms involved in liver fibrosis could provide valuable insights into developing new treatments for chronic liver diseases,although the current evidence is still controversial.This review provides a comprehensive summary of the regulatory mechanisms and critical targets of epigenetic modifications,including DNA methylation,histone modification,and RNA modification,in liver fibrotic diseases.The potential cooperation of different epigenetic modifications in promoting fibrogenesis was also highlighted.Finally,available agonists or inhibitors regulating these epigenetic mechanisms and their potential application in preventing liver fibrosis were discussed.In summary,elucidating specific druggable epigenetic targets and developing more selective and specific candidate medicines may represent a promising approach with bright prospects for the treatment of chronic liver diseases.

Histone deacetylase HDA710 controls salt tolerance by regulating ABA signaling in rice

Plants have evolved numerous mechanisms that assist them in withstanding environmental stresses.Histone deacetylases(HDACs)play crucial roles in plant stress responses;however,their regulatory mechanisms remain poorly understood.Here,we explored the function of HDA710/OsHDAC2,a member of the HDAC RPD3/HDA1 family,in stress tolerance in rice(Oryza sativa).We established that HDA710 localizes to both the nucleus and cytoplasm and is involved in regulating the acetylation of histone H3 and H4,specifically targeting H4 K5 and H4 K16 under normal conditions.HDA710 transcript accumulation levels were strongly induced by abiotic stresses including drought and salinity,as well as by the phytohormones jasmonic acid(JA)and abscisic acid(ABA).hda710 knockout mutant plants showed enhanced salinity tolerance and reduced ABA sensitivity,whereas transgenic plants overexpressing HDA710 displayed the opposite phenotypes.Moreover,ABAand salt-stress-responsive genes,such as OsLEA3,OsABI5,OsbZIP72,and OsNHX1,were upregulated in hda710 compared with wild-type plants.These expression differences corresponded with higher levels of histone H4 acetylation in gene promoter regions in hda710 compared with the wild type under ABA and salt-stress treatment.Collectively,these results suggest that HDA710 is involved in regulating ABA-and salt-stress-responsive genes by altering H4 acetylation levels in their promoters.

The CBP/p300 histone acetyltransferases function as plant-specific MEDIATOR subunits in Arabidopsis

In eukaryotes,MEDIATOR is a conserved multisubunit complex that links transcription factors and RNA polymerase II and that thereby facilitates transcriptional initiation.Although the composition of MEDIATOR has been well studied in yeast and mammals,relatively little is known about the composition of MEDIATOR in plants.By affinity purification followed by mass spectrometry,we identified 28 conserved MEDIATOR subunits in Arabidopsis thaliana,including putative MEDIATOR subunits that were not previously validated.Our results indicated that MED34,MED35,MED36,and MED37 are not Arabidopsis MEDIATOR subunits,as previously proposed.Our results also revealed that two homologous CBP/p300 histone acetyltransferases,HAC1 and HAC5(HAC1/5)are in fact plant-specific MEDIATOR subunits.The MEDIATOR subunits MED8 and MED25(MED8/25)are partially responsible for the association of MEDIATOR with HAC1/5,MED8/25 and HAC1/5 co-regulate gene expression and thereby affect flowering time and floral development.Our in vitro observations indicated that MED8 and HAC1 form liquid-like droplets by phase separation,and our in vivo observations indicated that these droplets co-localize in the nuclear bodies at a subset of nuclei.The formation of liquid-like droplets is required for MED8 to interact with RNA polymerase II.In summary,we have identified all of the components of Arabidopsis MEDIATOR and revealed the mechanism underlying the link of histone acetylation and transcriptional regulation.

Three functionally redundant plant-specific paralogs are core subunits of the SAGA histone acetyltransferase complex in Arabidopsis

The SAGA(Spt-Ada-Gcn5 acetyltransferase)complex is an evolutionarily conserved histone acetyltransferase complex that has a critical role in histone acetylation,gene expression,and various developmental processes in eukaryotes.However,little is known about the composition and function of the SAGA complex in plants.In this study,we found that the SAGA complex in Arabidopsis thaliana contains not only conserved subunits but also four plant-specific subunits:three functionally redundant paralogs,SCSI,SCS2A,and SCS2B(SCS1/2A/2B),and a TAF-like subunit,TAFL.Mutations in SCS1/2A/2B lead to defective phenotypes similar to those caused by mutations in the genes encoding conserved SAGA subunits HAG1 and ADA2B,including delayed juvenile-to-adult phase transition,late flowering,and increased trichome density.Furthermore,we demonstrated that SCS1/2A/2B are required for the function of the SAGA complex in histone acetylation,thereby promoting the transcription of development-related genes.These results together suggest that SCS1/2A/2B are core subunits of the SAGA complex in Arabidopsis.Compared with SAGA complexes in other eukaryotes,the SAGA complexes in plants have evolved unique features that are necessary for normal growth and development.

Gestational dexamethasone exposure impacts hippocampal excitatory synaptic transmission and learning and memory function with transgenerational effects

The formation of learning and memory is regulated by synaptic plasticity in hippocampal neurons.Here we explored how gestational exposure to dexamethasone,a synthetic glucocorticoid commonly used in clinical practice,has lasting effects on offspring's learning and memory.Adult offspring rats of prenatal dexamethasone exposure(PDE)displayed significant impairments in novelty recognition and spatial learning memory,with some phenotypes maintained transgenerationally.PDE impaired synaptic transmission of hippocampal excitatory neurons in offspring of F1 to F3 generations,and abnormalities of neurotransmitters and receptors would impair synaptic plasticity and lead to impaired learning and memory,but these changes failed to carry over to offspring of F5 and F7 generations.Mechanistically,altered hippocampal miR-133a-3p-SIRT1-CDK5-NR2B signaling axis in PDE multigeneration caused inhibition of excitatory synaptic transmission,which might be related to oocyte-specific high expression and transmission of miR-133a-3p.Together,PDE affects hippocampal excitatory synaptic transmission,with lasting consequences across generations,and CDK5 in offspring's peripheral blood might be used as an early-warning marker for fetal-originated learning and memory impairment.