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Peroxisomal Β-Oxidation Regulates Histone Acetylation and DNA Methylation in Arabidopsis

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Peroxisomal Β-Oxidation Regulates Histone Acetylation and DNA Methylation in Arabidopsis Peroxisomal β-oxidation regulates histone acetylation and DNA methylation in Arabidopsis Lishuan Wanga,1, Chunlei Wangb,1, Xinye Liuc, Jinkui Chenga, Shaofang Lia, Jian-Kang Zhud,e,2, and Zhizhong Gonga,2 aState Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, 100193 Beijing, China; bCollege of Horticulture, Gansu Agricultural University, 730070 Lanzhou, China; cMinistry of Education Key Laboratory of Molecular and Cellular Biology, College of Life Sciences, Hebei Normal University, 050024 Shijiazhuang, China; dShanghai Center for Plant Stress Biology, National Key Laboratory of Plant Molecular Genetics, Center of Excellence in Molecular Plant Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 200032 Shanghai, China; and eDepartment of Horticulture and Landscape Architecture, Purdue University, West Lafayette, IN 47907 Contributed by Jian-Kang Zhu, April 4, 2019 (sent for review March 12, 2019; reviewed by Bao Liu and Jim Peacock) Epigenetic markers, such as histone acetylation and DNA methylation, DNA methylation is a conserved epigenetic marker important determine chromatin organization. In eukaryotic cells, metabolites in genome organization, gene expression, genomic imprinting, from organelles or the cytosol affect epigenetic modifications. How- paramutation, and X chromosome inactivation in organisms (3, ever, the relationships between metabolites and epigenetic modifica- 11–13). DNA methylation patterns are coordinately determined tions are not well understood in plants. We found that peroxisomal by methylation and demethylation reactions in plants and ani- acyl-CoA oxidase 4 (ACX4), an enzyme in the fatty acid β-oxidation mals (13, 14). The active removal of 5mC in Arabidopsis is car- pathway, is required for suppressing the silencing of some endoge- ried out by a subfamily of bifunctional DNA glycosylases/lyases nous loci, as well as Pro35S:NPTII in the ProRD29A:LUC/C24 transgenic represented by REPRESSOR OF SILENCING 1 (ROS1) and line. The acx4 mutation reduces nuclear histone acetylation and in- DEMETER (DME) (15, 16). ROS1 family proteins bind DNA non- creases DNA methylation at the NOS terminator of Pro35S:NPTII and specifically (17) and need other factors to find target genomic regions at some endogenous genomic loci, which are also targeted by the (13). Among these, ROS4/INCREASED DNA METHYLATION 1 demethylation enzyme REPRESSOR OF SILENCING 1 (ROS1). Further- (IDM1) is a plant homeodomain finger-containing histone more, mutations in multifunctional protein 2 (MFP2) and 3-ketoacyl- acetyltransferase that catalyzes the acetylation of histone H3 CoA thiolase-2 (KAT2/PED1/PKT3), two enzymes in the last two steps lysine 18 (H3K18) and lysine 23 (H3K23) to create a favorable of the β-oxidation pathway, lead to similar patterns of DNA hyper- chromatin environment for the recruitment of ROS1 at some methylation as in acx4. Thus, metabolites from fatty acid β-oxidation loci(1,18).ROS4/IDM1,togetherwith other factors, such as ROS5/ in peroxisomes are closely linked to nuclear epigenetic modifications, IDM2, IDM3, methyl-CPG-binding domain 7 (MBD7), Harbinger which may affect diverse cellular processes in plants. Significance β-oxidation | acetyl-CoA | histone acetylation | DNA methylation | gene silencing Small-molecule metabolites from cell organelles or cytosol exert their influence on decision making processes in eukaryotic cells. istone acetylation is important for neutralizing the positive However, the mechanisms underlying the regulation of cellular Hcharges of lysine residues and promoting chromatin relaxation; processes by these metabolites are not well understood. Among it is also required for transcription, DNA replication, histone these small metabolites, acetyl-CoA, a most critical one, is pro- – methylation, and other histone modifications (1 4). Histones are duced in the cytosol and different cell organelles. In plants, acetyl- acetylated by acetyltransferases, which transfer acetyl groups CoA produced from fatty acid β-oxidation in peroxisomes plays from acetyl-CoA to histone lysine residues. critical roles in various developmental stages. Here we found that Acetyl-CoA is a central metabolite that can be produced via defects in β-oxidation in peroxisomes affect both histone acety- several metabolic pathways involved in pyruvate, citrate, acetate, lation and DNA methylation in the nucleus. Our work provides β and fatty acid -oxidation metabolism (5). In mammals, acetyl- evidence for retrograde signaling from peroxisomes to regulate CoA in mitochondria is produced from different pathways, in- nuclear epigenetic modifications in higher eukaryotes. cluding the fatty acid β-oxidation (6). In cytosol and nucleus, adenosine triphosphate (ATP)-citrate lyase (ACLY) cleaves Author contributions: L.W., C.W., J.-K.Z., and Z.G. designed research; L.W. and C.W. per- citrate exported from mitochondria to regenerate acetyl-CoA formed research; L.W., C.W., X.L., J.C., and S.L. analyzed data; and L.W., J.-K.Z., and Z.G. that can be used for other biosynthetic processes, such as fatty wrote the paper. acid synthesis and histone acetylation (6). In mouse, conditional Reviewers: B.L., Northeast Normal University; and J.P., Commonwealth Scientific and In- loss of carnitine palmitoyltransferase 1A (CPT1A), which is required dustrial Research Organisation. for the transfer of fatty acid into mitochondria for β-oxidation, The authors declare no conflict of interest. impairs dermal lymphatic formation via histone acetylation in an Published under the PNAS license. ACLY-dependent manner (7). A pyruvate dehydrogenase com- Data deposition: Sequence data referred to in this article have been deposited in the plex can be translocated from mitochondria to nuclei to generate GenBank/EMBL database (accession nos. AT2G36490 for ROS1, AT3G14980 for ROS4/ IDM1, AT5G66750 for DDM1, AT4G11130 for RDR2, AT3G51840 for ACX4, AT3G06860 acetyl-CoA and mediate histone acetylation in mammalian cells for MFP2, AT2G33150 for KAT2, AT1G64230 for UBC28, and AT3G18780 for ACTIN2). in certain conditions (2, 8). In Arabidopsis, the mutations in cytosolic Primary datasets for the whole-genome bisulfite sequences of Col-0, ros1-4, acx4-4, acetyl-CoA carboxylase (ACC1), which converts cytosolic acetyl- acx4-1, mfp2-2, and kat2-3 mutant plants have been deposited in the Gene Expression CoA to malonyl-CoA for elongating the plastid-produced fatty Omnibus (GEO) database (accession no. GSE98214). Histone acetylation ChIP-seq data also have been deposited in the GEO database (accession no. GSE98214). Whole-genome bi- acids, lead to high accumulation of cytosolic acetyl-CoA, spe- sulfite sequencing data of C24 WT, ros1-1, and ros4 plants were obtained from the GEO cifically resulting in increased H3K27 acetylation (H3K27ac) (9). database (accession no. SRP042060). These results underscore the importance of acetyl-CoA in 1L.W. and C.W. contributed equally to this work. histone acetylation in nuclei in both mammals and plants. However, 2To whom correspondence may be addressed. Email: [email protected] or gongzz@cau. in plant cells, plastids, mitochondria, peroxisomes, and cytosol can edu.cn. produce acetyl-CoA (10). Whether impairment of metabolism in This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. plant organelles will affect the nuclear epigenetic modifications is 1073/pnas.1904143116/-/DCSupplemental. still being unraveled. Published online May 7, 2019. 10576–10585 | PNAS | May 21, 2019 | vol. 116 | no. 21 www.pnas.org/cgi/doi/10.1073/pnas.1904143116 Downloaded by guest on September 27, 2021 transposon-derived protein 1 (HDP1), and HDP2, forms a complex to regulate active DNA demethylation (19–23). MET18 is a com- ponent in the cytosolic iron-sulfur cluster assembly pathway in- volved in the transfer of the Fe-SclustertoROS1,whichis necessary for its function (24). The expression of ROS1 is positively regulated by promoter DNA methylation, which requires a protein complex composed of Su(var)3–9 homologs (SUVHs) and SUVH- interacting DNAJ (SDJ) proteins (25–28). To identify the components required to prevent transgene si- lencing and normal DNA methylation patterns in Arabidopsis,we performed a forward genetic screen for kanamycin (Kan)-sensitive mutants using the ProRD29A:LUC/Pro35S:NPTII transgenic C24 line (18). Several ROS1 alleles, multiple components of the RdDM pathway,ROS4/IDM1,ROS5/IDM2, and MBD7, were identified in this screening (1, 18, 22, 23). Here we identified an antisilencing factor, acyl-CoA oxidase 4 (ACX4), in the fatty acid β-oxidation pathway. In acx4 mutants, overall levels of H3Ac and H4Ac are reduced, and DNA methylation is increased at some genomic loci, resulting in enhanced transcriptional silencing of reporter and some endogenous genes. The mfp2 and kat2 mutants have similar DNA hypermethylation phenotypes to acx4. Our results uncover a con- nection between fatty acid β-oxidation and epigenetic regulation in plants. Fig. 1. Characterization of the acx4 mutant. (A) The acx4 mutation silenced Results Pro35S:NPTII, as indicated by Kan sensitivity. The acx4-4, ros1-1, and ros4 ACX4 Is a Suppressor of Transcriptional Silencing. To decipher the mutants were grown on MS medium or on MS medium supplemented mechanism that blocks transcriptional gene silencing, we per- with 50 mg/L Kan. (B) The acx4 mutation does not affect the expression of ProRD29A:LUC. The acx4-4, ros1-1, and ros4 mutants grown on MS
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