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

Significance

In metazoans, pausing of Pol II during early elongation is a widespread regulatory mechanism for transcription regulation. However, preinitiation complex (PIC) assembly is more important for transcription in plants. Chromatin remodeling and histone modifications are considered important for access of protein factors to the underlying DNA sequences. However, how histone modifications are specifically and timely generated at active promoters is less understood. COMPASS-like complex plays a critical role in PIC assembly and histone H3K4 trimethylation. We found that Arabidopsis transcription factors bZIP28/bZIP60 interact with COMPASS-like components both in vitro and in vivo. We present a general model on how histone H3K4 trimethylation is specifically formed during inducible gene expression by using the endoplasmic reticulum (ER) stress response system in Arabidopsis plants.

Keywords: COMPASS-like, ER stress, H3K4 trimethylation, transcription factor, unfolded protein response

Abstract

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.

Packing of DNA with histone octamer into chromatin provides a sophisticated regulatory module for diverse gene regulation patterns in response to external environmental or internal developmental cues in eukaryotic cells (1). Posttranslational modifications of histones directly or indirectly regulate chromatin state, and they therefore are important for gene expression and heterochromatin silencing (2–4). For example, acetylation in the globular core histone H3 enables recruitment of the SWI/SNF nucleosome remodeling complex to facilitate gene transcription in yeast (5, 6). In contrast, histone H3 methylation does not affect chromatin structure per se, but interacts with additional factors such as the Complex Proteins Associated with Set1/Set1 Complex (COMPASS)/SET1C in yeast (7) or COMPASS-like complex in mammals (8), which contains three structural core components BRE2/Ash2, SWD3/WDR5, and SWD1/RbBP5, and H3K4 methyltransferases such as Set1 in yeast or MLL1 in mammals (8). Recently, the COMPASS-like complex was also reported to be well conserved in Arabidopsis plants (9).

Genome-wide chromatin immunoprecipitation analysis reveals that there is a strong correlation between histone H3K4 trimethylation (H3K4me3) and active gene expression in yeast (10), mammal (11, 12), and plants (13, 14). Despite the controversy on whether histone H3K4me3 conferred by the Trithorax family proteins promotes gene transcription, more experiments favor that H3K4me3 modification is the cause of gene transcription (15, 16). Depletion of histone H3K4me3 affects the expression of specific genes in yeast, mammals, and plants (9, 17–19), although depletion of H3K4me3 has little effect on global gene expression in yeast (18). Further study in Arabidopsis has demonstrated that the COMPASS-like complex not only facilitates transcription preinitiation complex (PIC) assembly, but also generates trimethylated histone at H3K4 that is important for gene-specific transcription (20). In human cells, trimethylated histone at H3K4 interacts with TAF3, part of the basal transcription factor TFIID, to direct global TFIID recruitment to active genes, some of which are p53 targets (21, 22). In vitro studies with recombinant chromatin and purified human factors showed a causal role for COMPASS/SET1C-mediated H3K4me3 in p53-dependent transcription (23). However, how histone modification complex is specifically and timely recruited to the promoters to potentiate active gene expression remains unanswered. We have studied this question by using the stress responsive gene expression system that is triggered by the accumulation of unfoled or misfolded proteins in the endoplasmic reticulum (ER).

Protein folding is fundamentally important for eukaryotic cells. A collection of conserved signaling pathways, termed the unfolded protein response (UPR), monitors protein folding status in the ER, and coordinates protein folding capacity with protein folding demands according to different developmental programs and environmental conditions (24–26). For gene transcriptional control, two ER-membrane-associated transcription factors, ATF6 and XBP1, play important roles in UPR in animal cells (27). These proteins reside on the ER membrane under normal condition. When unfolded or misfolded proteins accumulate in the ER, ATF6 is translocated from ER to Golgi apparatus, where it is sequentially cleaved by S1P and S2P proteases, and the N terminus containing the DNA binding and transcriptional activation domains enters the nucleus to activate downstream gene expression (28). Activation mechanism of XBP1 is similar to that of Hac1 in yeast in which IRE1-regulated unconventional splicing results in an ORF shift and elimination of the transmembrane domain, enabling the nuclear localization of the newly encoded XBP1 (29, 30). Using the model plant Arabidopsis, two ER membrane-associated transcription factors, bZIP28 and bZIP60, were identified as the plant counterparts of mamalian ATF6 and XBP1, which are activated through the regulated intramembrane proteolysis and unconventional splicing in response to ER stress, respectively (31–33). In general, when the membrane-associated transcription factors are activated, they recruit general transcription factors (GTFs) and RNA polymerase II (RNAPII) machinery (34) to the promoters of ER stress-responsive genes during transcription activation. For these protein factors to access the promoter DNA, physical barriers formed by chromatin must be altered through histone modifiers or chromatin remodeling factors . However, how the histone modification marks are deposited at specific target sites has not yet been answered. We found that sequence-specific transcription factors interract with COMPASS-like components Ash2 and WDR5a that are important for histone H3K4 trimethylation at specific promoters.

Results and Discussion

bZIP28 and bZIP60 Are Master Transcriptional Regulators in Plant UPR.

Previously we and other coworkers demonstrated the important roles of bZIP28 and bZIP60 in the plant UPR (31, 32). Beside the formation of bZIP28 homodimer and bZIP60 homodimer, bZIP28 could also interact with bZIP60 in the yeast two-hybrid assay (35), in vitro pull-down assay (Fig. S1 A and B), and bimolecular fluorescence complementation (BiFC) assay in tobacco (Nicotiana benthamiana) (Fig. S1C). Knockouts of both bZIP28 and bZIP60 in the double mutant zip28zip60 confer hypersensitivity to ER stress (Fig. S2) (36). In order to know whether bZIP28 and bZIP60 are prerequisite to induce UPR downstream gene expression in Arabidopsis, we compared the ER stress-regulated gene expression profiles of the wild-type (wt) and zip28zip60 plants with the Agilent oligo microarray (V4). Of the 4 × 44 K probes represented on the microarray, 333 probes representing 286 genes were up-regulated [fold change (FC) ≥ 2, P ≤ 0.05] by ER stress inducer tunicamycin (TM) in the wt plants (Fig. 1A and Dataset S1). However, only 6 probes representing 10 genes among them were up-regulated (FC ≥ 2, P ≤ 0.05) by ER stress in the zip28zip60 mutant plants (Fig. 1 A and B), of which the fold changes of two probes/genes in the zip28zip60 plants were greatly reduced to less than 50% of that in the wt plants (Dataset S1). There were 48 probes representing 46 genes that were up-regulated (FC ≥ 2, P ≤ 0.05) by ER stress specifically in the zip28zip60 plants, many of them are involved in iron uptake and iron metabolism (Fig. 1A and Dataset S1). ER stress also down-regulated (FC ≤ 0.5, P ≤ 0.05) 170 and 218 genes in the wt and zip28zip60 plants, respectively (Fig. 1A and Dataset S2). Eight ER stress up-regulated genes from the top list (Dataset S1) were selected, and their expression levels were checked with quantitative RT-PCR (RT-qPCR) to validate the microarray results. It was found that except At3g54550 and At3g12430, whose signal intensities on the microarray were relatively low in all of the tested samples (Dataset S1), another six genes were highly up-regulated by ER stress in the wt, which were greatly impaired in the zip28zip60 plants (Fig. 1C). These results demonstrated that bZIP28 and bZIP60 regulate most, if not all, of the downstream genes during the adaptive phase of UPR in Arabidopsis.

Fig. 1.

Fig. 1.

bZIP28 and bZIP60 are required for transcriptional regulation of ER stress responsive genes. (A) Venn diagrams of the numbers of overlapping and nonoverlapping up-regulated or down-regulated genes from the Arabidopsis Agilent oligo microarray (V4) after treatment with TM (5 µg/mL, 4 h) in the wt and zip28zip60 plants meeting of the criteria P ≤ 0.05, fold change (FC) ≥ 2 (for up-regulation) or FC ≤ 0.5 (for down-regulation). (B) Heat map of differentially up-regulated genes in the wt and zip28zip60 plants from the microarray experiment. FC is the value in the TM-treated sample (+TM) divided by that in the nontreated sample (−TM). Only those genes with 3 ≤ FC ≤ 10 (P ≤ 0.05) in the wt were used for heat map visualization. Each horizontal bar represents a single microarray probe. Green indicates a relatively low level of up-regulation, whereas red indicates a relatively high level of up-regulation. (C) RT-qPCR validation of the microarray results. Relative gene expression is the value of plants treated with TM (5 µg/mL, 4 h) divided by that of nontreated plants, both of which were normalized to the expression of actin. Bars depict SEM (n = 3).

Loss-of-Function Mutations in bZIP28 and bZIP60 Impair Histone H3K4 Trimethylation at Promoters of UPR Genes.

To better understand whether bZIP28 and bZIP60 directly bind to promoters of UPR downstream genes, chromatin immunoprecipitation (ChIP) experiments were carried out with commercial anti-MYC antibody by using transgenic plants overexpressing MYC-bZIP28 and MYC-bZIP60, in which ER stress induces the activation and nuclear location of both MYC-bZIP28 and MYC-bZIP60 (31, 37). qPCR was performed with primers flanking promoter regions of six genes as mentioned above (Fig. S3A). It turned out that during TM-induced ER stress, both MYC-bZIP28 and MYC-bZIP60 were enriched at the promoters of BiP3, TIN1, and ERDJ3A; MYC-bZIP28 was specifically enriched at the promoter of SARA1A, whereas MYC-bZIP60 was specifically enriched at the promoter of SEC31A (Fig. 2 A and B). ER stress did not induce the enrichment of either MYC-bZIP28 or MYC-bZIP60 at the promoters of NSF, or on the coding region and 3′ UTR region of BiP3 (Fig. 2 A and B). NSF might be the direct target of other transcription factors downstream of bZIP28/bZIP60 such as NAC103 (36). Taken together, our ChIP-qPCR results demonstrate that both bZIP28 and bZIP60 are able to directly bind to the promoter of several UPR genes and share some of the direct targets. It is established that histone H3K4 trimethylation at promoters and 5′-end regions significantly correlates with active gene expression (11, 13, 38, 39). By ChIP-qPCR with antibody against trimethylated histone at H3K4, we found that ER stress gradually induced H3K4me3 deposition at the promoters of UPR downstream genes (BiP3, SEC31A, NSF, TIN1, ERDJ3A, and SARA1A) in the wt plants (Fig. 2C). We also checked the pattern of monomethylation, dimethylation, and trimethylation of histone at H3K4 in the zip28zip60 double mutant plants as well as in the wt plants. Interestingly, the ER stress-induced H3K4me3 at promoters of above-mentioned UPR genes were abolished in the zip28zip60 double mutant (Fig. 2D). However, mutations of bZIP28 and bZIP60 did not have much effect on histone H3K4 dimethylation (H3K4me2) but affected ER stress-induced decrease of histone H3K4 monomethylation (H3K4me1) at promoters of these UPR genes (Fig. S3 A–C). Thus, gene-specific transcription factors bZIP28 and bZIP60 are not only important for up-regulation of UPR gene expression, but also correlated with histone H3K4me3 at promoters of strongly induced UPR genes.

Fig. 2.

Fig. 2.

Loss-of-function mutations of bZIP28 and bZIP60 impair enrichment of histone H3K4 trimethylation on ER stress target genes. (A and B) Direct bindings of bZIP28 or bZIP60 to the promoters of ER stress responsive genes in ChIP-qPCR assays. (C and D) Enrichment of trimethylated histone at H3K4 on ER stress responsive gene. Plants were treated with TM (5 µg/mL) for 6 h in A, B, and D. Fold change is the DNA enrichment normalized to the nontreated wt control sample, both of which were normalized to the level of actin. Primers at position a (Fig. S3A) were used for SEC31A, NSF, TIN1, ERDJ3A, and SARA1A. Bars depict SEM (n = 3).

bZIP28 and bZIP60 Interact with COMPASS-Like Complex.

In yeast and mammals, and in plants, histone H3K4 methylation is catalyzed by the COMPASS or COMPASS-like H3K4 methyltransferase complex (7, 9, 40–42). In Arabidopsis, the COMPASS-like complex containing Ash2/ASH2R, WDR5a/WDR5, and RbBP5/RBL deposits trimethylated but not dimethylated or monomethylated histone at H3K4 to the target genes to promote gene expression for flowering control (9). Because the ER stress-induced histone H3K4me3 at UPR gene promoters was impaired in the zip28zip60 plants, we were interested in the possible interactions between the transcription factors (bZIP28 and/or bZIP60) and components in COMPASS-like complex (Ash2, WDR5a, and/or RbBP5). His- or MBP-tagged forms of Ash2, WDR5a, and RbBP5 were purified from Escherichia coli and tested for the interactions between COMPASS-like components and the available derivates of bZIP28 or bZIP60 in the in vitro pull-down assays (Fig. 3A). It was found that the activated forms of both bZIP28 and bZIP60 could pull down Ash2 or WDR5a (Fig. 3B). In contrast, neither bZIP28 nor bZIP60 pulled down RbBP5 (Fig. 3B). To confirm these positive interactions obtained from pull-down assays, BiFC experiments were performed in tobacco leaves. It was found that both bZIP28 and bZIP60 were able to physically interact with Ash2 or WDR5a in tobacco plants (Fig. 3C). In contrast, interactions between transcription factor (bZIP28 or bZIP60) and RbBP5 were not observed (Fig. 3C). Further truncation experiment demonstrated that the DNA binding domain of bZIP28 (amino acids 138–256) was sufficient for its interaction with Ash2 or WDR5a in the BiFC assays (Fig. S4 A and B). The interaction between transcription factor and COMPASS-like appears to be general, because another ER-stress-related transcription factor NAC103 (36) also interacts with Ash2 and WDR5a in the BiFC experiment (Fig. S4C).

Fig. 3.

Fig. 3.

bZIP28 and bZIP60 interact with COMPASS-like complex. (A) Schematic structure of bZIP28, bZIP60, and their derivates. The transcriptional activation domain (TAD), DNA-binding domain (DBD), and transmembrane domain (TMD) are shown. (B) In vitro pull-down assays for the interactions between transcription factors and COMPASS-like components. Various fusion proteins were purified from E. coli and used for GST pull-down assays. GST protein was used as a negative control. (C) In vivo BiFC assays for the interactions between transcription factors and COMPASS-like components. Various pairs of constructs were cotransformed into tobacco (N. benthamiana), and the tobacco epidermal cells were observed under laser confocal microscopy. (Scale bars: 50 μm.)

Knockdown Expression of Either Ash2 or WDR5a Affects the Expression of ER Stress Responsive Genes.

Previous research has shown that the COMPASS-like components play important roles in regulating flowering gene expression (9). To know whether these components also control the expression of ER stress responsive genes, RT-qPCR was performed with TM-treated or nontreated wt plants and RNAi mutants of Ash2 or WDR5a. It was found that knockdown expression of either Ash2 or WDR5a substantially decreased the up-regulation of ER stress responsive genes such as BiP3, SEC31A, NSF, TIN1, and SARA1A (Fig. 4 A and B). To investigate whether knockdown expression of Ash2 or WDR5a also affects enrichment of H4K4 trimethylated histone at UPR genes, CHIP-qPCR was performed. It was found that the ER stress-induced H3K4me3 was decreased at UPR genes such as BiP3 in RNAi plants of either Ash2 or WDR5a comparing to the wt plants (Fig. S5 A and B). The level of H3K4me3 was not much affected at other UPR genes such as ERDJ3A, which might be explained by the remained activity of Ash2 or WDR5a in the transgenic plants (Fig. S6 A–D). Thus, the COMPASS-like complex is also important for specific inducible gene expression during the ER stress response in plants.

Fig. 4.

Fig. 4.

Knockdown expression of either Ash2 or WDR5a affects the expression of ER stress responsive genes. (A and B) ER stress-induced expression of downstream genes in the wt and Ash2 or WDR5a RNAi plants. Fold change is the relative gene expression of plants treated with TM (5 µg/mL, 2 h) divided by that of nontreated plants, both of which were normalized to the expression of housekeeping gene actin. Bars depict SEM (n = 3).

Recruitment of RNAPII to UPR Gene Promoters Is Defective in the zip28zip60 Mutant Plants.

In addition to the important roles of COMPASS-like in the assembly of basal transcription machinery, COMPASS-like complex also interacts with the phosphorylated carboxyl-terminal domain (CTD) of RNA polymerase II (RNAPII) after PIC assembly in Arabidopsis (20). Further analysis demonstrates that both H3K4 methyltransferase ATX1 and COMPASS-like are required for high-level accumulations of RNAPII and H3K4me3 on ATX1/COMPASS-like regulated genes (20). Therefore, we also examined the occupancy of total RNAPII at above-mentioned UPR genes in both the wt and zip28zip60 double mutant plants. ChIP-qPCR results showed that ER stress induced the enrichment of RNAPII at promoters and coding regions of six aforementioned UPR genes in the wt plants (Fig. 5 A and B). However, such ER stress-induced enrichments of RNAPII were not observed in the zip28zip60 double mutants (Fig. 5 A and B). These results showed that sequence-specific transcription factors are important for total RNAPII recruitment during inducible gene expression.

Fig. 5.

Fig. 5.

Loss-of-function mutations of bZIP28 and bZIP60 affect RNAPII occupancy on UPR gene promoters. (A and B) Enrichment of total RNAPII to the promoters (A) or coding regions (B) of ER stress responsive genes in ChIP-qPCR assays. Fold change is the DNA enrichment normalized to the nontreated (−TM) wt control sample. The wt and zip28zip60 mutant plants were treated with TM (5 µg/mL, 6 h) and anti-Pol II antibody was used to precipitate RNAPII. Primer position refers to Fig. S3A. Bars depict SEM (n = 3).

Conclusions

Recently, computational analysis combined with chromatin immunoprecipitation followed by sequencing (ChIP-Seq) revealed that transcription factor binding predicts histone modifications in human cell lines (43), but the role of transcription factor in histone modifications over specific gene promoters has not been experimentally demonstrated. Our data showed that sequence-specific transcription factor regulates gene expression not only by recognizing specific DNA sequences, but also by facilitating histone modifications such as H3K4me3 at specific DNA sites through interaction with the COMPASS-like components Ash2 and WDR5a (Fig. 6). Because the COMPASS-like complex is known to facilitate PIC assembly and generate H3K4me3, the data presented here provide evidence on understanding the deposition of histone H3K4me3 mark at specific target sites for inducible gene expression in plants. Such regulation is particularly important because much of stress-responsive gene expression in metazoans is mediated at the level of transcription elongation (44) whereas plants lack components of promoter proximal pausing, and the Arabidopsis ATX1/COMPASS-like regulated genes lack preaccumulated Pol II at their 5′ ends (20).

Fig. 6.

Fig. 6.

A hypothetical model for the involvement of transcription factor in histone modification. During the preinitiation complex (PIC) assembly for transcriptional control in plant UPR, both sequence-specific transcription factor (TF) bZIP28 or bZIP60 and general transcription factors (GTFs) are recruited to the promoters together with the TATA-box binding protein (TBP) and the mediator. Meanwhile, transcription factor bZIP28 or bZIP60 interacts with the COMPASS-like components Ash2 or WDR5a to facilitate the interraction between COMPASS-like and histone trimethytransferases. Such interaction may generate histone H3K4me3 at promoter regions of UPR genes. ATX1/COMPASS-like also interracts with the CTD of Pol II, and the level of H3K4me3 affects the rate of Pol II exit for transcription elongation. Other chromatin modifiers such as chromatin remodeling factors and histone acetyltransferases may also play important roles in this process.

Materials and Methods

Plant Materials and Growth Condition.

All of the Arabidopsis thaliana seeds used in this study were in the Col background. Plants were grown at 22 °C under white light in a long-day (16-h light/8-h darkness) light photoperiod. Details for generation of RNAi plants are in SI Materials and Methods. For phenotypic analysis, plants were grown on half strength Murashige and Skoog (MS) plates containing 1% sucrose without or with tunicamycin (TM). For gene expression analysis and CHIP-qPCR, plants were first grown on half-strength MS plates containing 1% sucrose. Subsequently, seedlings were pulled out from the solid medium and subjected to treatments in liquid half-strength MS without or with TM.

Gene Expression Analysis and ChIP-qPCR.

Details are in SI Materials and Methods. All of the primers used for RT-qPCR and CHIP-qPCR are listed in Table S1.

In Vitro Pull-Down and in Vivo BiFC Assays.

Details are in SI Materials and Methods. Primers for various constructs are listed in Table S1.

Supplementary Material

Supplementary File

Supplementary File

Supplementary File

Acknowledgments

We thank Dr. Hongxing Yang for heat map visualization. This study was supported by National Basic Research Program of China 973 Program Grant 2012CB910500 and National Natural Science Foundation of China Grants 31171157, 31222008, and 31470353 (to J.X.L.).

Footnotes

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

Data deposition: The microarray data reported in the paper have been deposited in the ArrayExpress database, www.ebi.ac.uk/arrayexpress (accession no. E-MTAB-2657).

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