scholarly journals A unique GCN5 histone acetyltransferase complex controls erythrocyte invasion and virulence in the malaria parasite Plasmodium falciparum

2021 ◽  
Author(s):  
Jun Miao ◽  
Chengqi Wang ◽  
Amuza Lucky ◽  
Xiaoying Liang ◽  
Hui Min ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Transcription Factor ◽  
Histone Acetyltransferase ◽  
Cellular Processes ◽  
H3k4 Trimethylation ◽  
Erythrocyte Invasion ◽  
Histone Acetyltransferase Gcn5 ◽  
Parasitic Protist ◽  
Activator Complex

AbstractThe histone acetyltransferase GCN5-associated SAGA complex is evolutionarily conserved from yeast to human and functions as a general transcription co-activator in global gene regulation. In this study, we identified a divergent GCN5 complex in Plasmodium falciparum, which contains two plant homeodomain (PHD) proteins (PfPHD1 and PfPHD2) and a plant apetela2 (AP2)-domain transcription factor (PfAP2-LT). To dissect the functions of the PfGCN5 complex, we generated parasites with the bromodomain deletion in PfGCN5 and the PHD domain deletion in PfPHD1. The two deletion mutants closely phenocopied each other, exhibiting significantly reduced merozoite invasion of erythrocytes and elevated sexual conversion. These domain deletions caused dramatic decreases not only in histone H3K9 acetylation but also in H3K4 trimethylation, indicating synergistic crosstalk between the two euchromatin marks. Domain deletion in either PfGCN5 or PfPHD1 profoundly disturbed the global transcription pattern, causing altered expression of more than 60% of the genes. At the schizont stage, these domain deletions were linked to specific downregulation of merozoite genes involved in erythrocyte invasion, many of which harbor the DNA-binding motifs for AP2-LT and/or AP2-I, suggesting targeted recruitment of the PfGCN5 complex to the invasion genes by these specific transcription factors. Conversely, at the ring stage, PfGCN5 or PfPHD1 domain deletions disrupted the mutually exclusive expression pattern of the entire var gene family, which encodes the virulent factor PfEMP1. Correlation analysis between the chromatin state and alteration of gene expression demonstrated that up- and down-regulated genes in these mutants are highly correlated with the silenct and active chromatin states in the wild-type parasite, respectively. Collectively, the PfGCN5 complex represents a novel HAT complex with a unique subunit composition including the AP2 transcription factor, which signifies a new paradigm for targeting the co-activator complex to regulate general and parasite-specific cellular processes in this low-branching parasitic protist.Author SummaryEpigenetic regulation of gene expression plays essential roles in orchestrating the general and parasite-specific cellular pathways in the malaria parasite Plasmodium falciparum. Using tandem affinity purification and proteomic characterization, we identified a divergent transcription co-activator – the histone acetyltransferase GCN5-associated complex in P. falciparum, which contains nine core components, including two PHD domain proteins (PfPHD1 and PfPHD2) and a plant apetela2-domain transcription factor. To understand the functions of the PfGCN5 complex, we performed gene disruption in two subunits of this complex, PfGCN5 and PfPHD1. We found that the two deletion mutants displayed very similar growth phenotypes, including significantly reduced merozoite invasion rates and elevated sexual conversion. These two mutants were associated with dramatic decreases in histone H3K9 acetylation and H3K4 trimethylation, which led to global changes in chromatin states and gene expression. Genes significantly affected by the PfGCN5 and PfPHD1 gene disruption include those participating in parasite-specific pathways such as invasion, virulence, and sexual development. In conclusion, this study presents a new model of the PfGCN5 complex for targeting the co-activator complex to regulate general and parasite-specific cellular processes in this low-branching parasitic protist.

scholarly journals A unique GCN5 histone acetyltransferase complex controls erythrocyte invasion and virulence in the malaria parasite Plasmodium falciparum

2021 ◽  
Vol 17 (8) ◽  
pp. e1009351
Author(s):  
Jun Miao ◽  
Chengqi Wang ◽  
Amuza Byaruhanga Lucky ◽  
Xiaoying Liang ◽  
Hui Min ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Transcription Factor ◽  
Histone Acetyltransferase ◽  
Binding Motif ◽  
Saga Complex ◽  
New Paradigm ◽  
Altered Expression ◽  
Erythrocyte Invasion ◽  
Histone Acetyltransferase Gcn5 ◽  
In The Wild

The histone acetyltransferase GCN5-associated SAGA complex is evolutionarily conserved from yeast to human and functions as a general transcription co-activator in global gene regulation. In this study, we identified a divergent GCN5 complex in Plasmodium falciparum, which contains two plant homeodomain (PHD) proteins (PfPHD1 and PfPHD2) and a plant apetela2 (AP2)-domain transcription factor (PfAP2-LT). To dissect the functions of the PfGCN5 complex, we generated parasite lines with either the bromodomain in PfGCN5 or the PHD domain in PfPHD1 deleted. The two deletion mutants closely phenocopied each other, exhibiting significantly reduced merozoite invasion of erythrocytes and elevated sexual conversion. These domain deletions caused dramatic decreases not only in histone H3K9 acetylation but also in H3K4 trimethylation, indicating synergistic crosstalk between the two euchromatin marks. Domain deletion in either PfGCN5 or PfPHD1 profoundly disturbed the global transcription pattern, causing altered expression of more than 60% of the genes. At the schizont stage, these domain deletions were linked to specific down-regulation of merozoite genes involved in erythrocyte invasion, many of which contain the AP2-LT binding motif and are also regulated by AP2-I and BDP1, suggesting targeted recruitment of the PfGCN5 complex to the invasion genes by these specific factors. Conversely, at the ring stage, PfGCN5 or PfPHD1 domain deletions disrupted the mutually exclusive expression pattern of the entire var gene family, which encodes the virulent factor PfEMP1. Correlation analysis between the chromatin state and alteration of gene expression demonstrated that up- and down-regulated genes in these mutants are highly correlated with the silent and active chromatin states in the wild-type parasite, respectively. Collectively, the PfGCN5 complex represents a novel HAT complex with a unique subunit composition including an AP2 transcription factor, which signifies a new paradigm for targeting the co-activator complex to regulate general and parasite-specific cellular processes in this low-branching parasitic protist.

scholarly journals Histone Acetyltransferase Inhibitor Anacardic Acid Causes Changes in Global Gene Expression during In Vitro Plasmodium falciparum Development

2008 ◽  
Vol 7 (7) ◽  
pp. 1200-1210 ◽  
Author(s):  
Long Cui ◽  
Jun Miao ◽  
Tetsuya Furuya ◽  
Qi Fan ◽  
Xinyi Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Histone Acetyltransferase ◽  
Global Gene Expression ◽  
Anacardic Acid ◽  
Obvious Effect ◽  
Nuclear Extracts ◽  
Resistant Strains

ABSTRACT To better understand the role of histone lysine acetylation in transcription in Plasmodium falciparum, we sought to attenuate histone acetyltransferase (HAT) activity using anacardic acid (AA). We showed that AA reversibly and noncompetitively inhibited the HAT activity of recombinant PfGCN5. To a lesser extent, AA inhibited the PfGCN5 activity in parasite nuclear extracts but did not affect histone deacetylase activity. AA blocked the growth of both chloroquine-sensitive and -resistant strains, with a 50% inhibitory concentration of ∼30 μM. Treatment of the parasites with 20 μM of AA for 12 h had no obvious effect on parasite growth or gross morphology but induced hypoacetylation of histone H3 at K9 and K14, but not H4 at K5, K8, K12, and K16, suggesting inhibition of the PfGCN5 HAT. Microarray analysis showed that this AA treatment resulted in twofold or greater change in the expression of 271 (∼5%) parasite genes in late trophozoites, among which 207 genes were downregulated. Cluster analysis of gene expression indicated that AA mostly downregulated active genes, and this gene pool significantly overlapped with that enriched for H3K9 acetylation. We further demonstrated by chromatin immunoprecipitation and real-time PCR that AA treatment reduced acetylation near the putative promoters of a set of downregulated genes. This study suggests that the parasiticidal effect of AA is at least partially associated with its inhibition of PfGCN5 HAT, resulting in the disturbance of the transcription program in the parasites.

scholarly journals Interferon Regulatory Factor 5 (IRF5) Interacts with the Translation Initiation Complex and Promotes mRNA Translation During the Integrated Stress Response to Amino Acid Deprivation

2017 ◽  
Author(s):  
James D. Warner ◽  
Mandi Wiley ◽  
Ying-Y Wu ◽  
Feng Wen ◽  
Michael Kinter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Stress Response ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Initiation Complex ◽  
Cellular Processes ◽  
Interferon Regulatory Factor 5

ABSTRACTInterferon Regulatory Factor 5 (IRF5) plays an important role in limiting pathogenic infection and tumor development. Host protection by IRF5 can occur through a variety of mechanisms including production of type I interferon and cytokines as well as the regulation of cell survival, growth, proliferation, and differentiation. While modulation of these cellular processes is attributed to IRF5 transcription factor function in the nucleus, emerging evidence suggests that IRF5 may also retain non-transcriptional regulatory properties within the cytoplasmic compartment. Consistent with this notion, we report the ability of IRF5 to control gene expression at the level of mRNA translation. Our findings demonstrate that IRF5 interacts with the translation initiation complex in the absence of the m7GTP cap-binding protein, eIF4E. We observed that under nutrient deprivation-induced cell stress, IRF5 promoted mRNA translation of the master integrated stress response (ISR) regulator, Activating Transcription Factor 4 (ATF4). Enhanced ATF4 protein expression correlated with increased levels of downstream target genes including CHOP and GADD34 and was associated with amplification of eIF2α de-phosphorylation and translational de-repression under stress. The novel mechanism we describe broadens our understanding of how IRF5 regulates gene expression and may govern diverse cellular processes in the absence of stimuli that trigger IRF5 nuclear translocation.

scholarly journals Transcription factor interaction with COMPASS-like complex regulates histone H3K4 trimethylation for specific gene expression in plants

2015 ◽  
Vol 112 (9) ◽  
pp. 2900-2905 ◽  
Author(s):  
Ze-Ting Song ◽  
Le Sun ◽  
Sun-Jie Lu ◽  
Yongke Tian ◽  
Yong Ding ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Er Stress ◽  
Gene Profiling ◽  
Bimolecular Fluorescence Complementation ◽  
Specific Gene ◽  
H3k4 Trimethylation ◽  
Histone H3k4 ◽  
Stress Responsive Genes

Accumulation of unfolded or misfolded proteins causes endoplasmic reticulum (ER) stress, which activates a set of ER membrane-associated transcription factors for protein homeostasis regulation. Previous genome-wide chromatin immunoprecipitation analysis shows a strong correlation between histone H3K4 trimethylation (H3K4me3) and active gene expression. However, how the histone modification complex is specifically and timely recruited to the active promoters remains unknown. Using ER stress responsive gene expression as a model system, we demonstrate that sequence-specific transcription factors interact with COMPASS-like components and affect H3K4me3 formation at specific target sites in Arabidopsis. Gene profiling analysis reveals that membrane-associated basic leucine zipper (bZIP) transcription factors bZIP28 and bZIP60 regulate most of the ER stress responsive genes. Loss-of-functions of bZIP28 and bZIP60 impair the occupancy of H3K4me3 on promoter regions of ER stress responsive genes. Further, in vitro pull-down assays and in vivo bimolecular fluorescence complementation (BiFC) experiments show that bZIP28 and bZIP60 interact with Ash2 and WDR5a, both of which are core COMPASS-like components. Knockdown expression of either Ash2 or WDR5a decreased the expression of several ER stress responsive genes. The COMPASS-like complex is known to interact with histone methyltransferase to facilitate preinitiation complex (PIC) assembly and generate H3K4me3 during transcription elongation. Thus, our data shows that the ER stress stimulus causes the formation of PIC and deposition of H3K4me3 mark at specific promoters through the interaction between transcription factor and COMPASS-like components.

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