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Ligand-Induced Gene Activation Is Associated with Oxidative Genome Damage Whose Repair Is Required for Transcription

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Ligand-Induced Gene Activation Is Associated with Oxidative Genome Damage Whose Repair Is Required for Transcription Ligand-induced gene activation is associated with oxidative genome damage whose repair is required for transcription Shiladitya Senguptaa,1,2,3, Haibo Wanga,b,1, Chunying Yanga,4, Bartosz Szczesnyc,d, Muralidhar L. Hegdea,b,e,2, and Sankar Mitraa,e,f,2 aDepartment of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030; bDepartment of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX 77030; cDepartment of Ophthalmology and Visual Sciences, The University of Texas Medical Branch, Galveston, TX 77555; dDepartment of Anesthesiology, The University of Texas Medical Branch, Galveston, TX 77555; eWeill Cornell Medical College, Cornell University, New York, NY 10065; and fHouston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX 77030 Edited by Sankar Adhya, National Institutes of Health, National Cancer Institute, Bethesda, MD, and approved July 16, 2020 (received for review November 6, 2019) .– m OH- Among several reversible epigenetic changes occurring during O2 ; the TETs oxidize 5 C to 5-hydroxymethyl cytosine (5 transcriptional activation, only demethylation of histones and mC) (12–14). The nuclear ROS generated from these demethy- cytosine-phosphate-guanines (CpGs) in gene promoters and other lation reactions are distinct from the extranuclear ROS gener- regulatory regions by specific demethylase(s) generates reactive ated primarily as mitochondrial respiration by-products and by oxygen species (ROS), which oxidize DNA and other cellular com- various oxidases in the endoplasmic reticulum, peroxisomes, and ponents. Here, we show induction of oxidized bases and single- .– plasma membrane (15–17). O2 is readily converted to H2O2 by strand breaks (SSBs), but not direct double-strand breaks (DSBs), in .– the ubiquitous superoxide dismutase (18). While H2O2 and O2 the genome during gene activation by ligands of the nuclear re- oxidize DNA and other cellular components, these ROS also ceptor superfamily. We observed that these damages were pref- react with each other in the presence of Fe2+ (Haber-Weiss re- erentially repaired in promoters via the base excision repair (BER)/ single-strand break repair (SSBR) pathway. Interestingly, BER/SSBR action) to form the highly reactive hydroxyl radical, which oxidizes – CELL BIOLOGY inhibition suppressed gene activation. Constitutive association all cellular components, including DNA (19 22). of demethylases with BER/SSBR proteins in multiprotein com- Here, we demonstrated that these nuclear ROS, generated plexes underscores the coordination of histone/DNA demethyla- via histone/CpG demethylation during ligand-induced gene ac- tion and genome repair during gene activation. However, ligand- tivation, caused DNA base oxidation and single-strand break independent transcriptional activation occurring during heat shock (SSB), but not direct double-strand break (DSB), in the genome. (HS) induction is associated with the generation of DSBs, the repair of which is likewise essential for the activation of HS-responsive Significance genes. These observations suggest that the repair of distinct dam- ages induced during diverse transcriptional activation is a univer- The endogenous genome damage induced by mitochondrial/ sal prerequisite for transcription initiation. Because of limited cytosolic reactive oxygen species (ROS) is well recognized. investigation of demethylation-induced genome damage dur- However, similar damage induced by nuclear ROS generated ing transcription, this study suggests that the extent of oxidative via histone/cytosine-phosphate-guanine (CpG) demethylation genome damage resulting from various cellular processes is during transcription has not been scrupulously investigated. substantially underestimated. This report documents the formation of genomic oxidized ba- ses and single-strand breaks during ligand-induced gene acti- transcriptional activation | histone demethylation | DNA demethylation | vation via histone/CpG demethylation. That repair of these oxidative genome damage | base excision/single-strand break repair damages occurs preferentially in promoters and is essential for transcriptional activation underscore the essentiality of hromatin remodeling during transcriptional reprogramming promoter-specific repair for transcription. In contrast, heat shock Cis associated with reversible covalent modifications, primar- (HS) induction generates double-strand breaks, the repair of ily acetylation and methylation at specific Lys/Arg residues which is essential for the activation of HS-responsive genes. in histones H3 and H4 and methylation at cytosines (Cs) in This study thus implies gross underestimation of endogenous cytosine-phosphate-guanine (CpG) dinucleotide clusters in gene oxidative genome damage and highlights the intrinsic diversity regulatory regions (e.g., promoters, enhancers) (1–6). Tran- of damage and distinct repair processes associated with scriptional activation involves acetylation of H3/H4 at specific transcription. Lys residues, usually in conjunction with the demethylation of H3 at Lys9. At the same time, 5-methyl cytosines (5mCs) in Author contributions: S.S., M.L.H., and S.M. designed research; S.S., H.W., C.Y., B.S., and M.L.H. performed research; S.S., H.W., C.Y., B.S., M.L.H., and S.M. analyzed data; and S.S. promoter CpG clusters and other regulatory regions are deme- and S.M. wrote the paper. thylated. Both protein and DNA demethylases carry out oxida- The authors declare no competing interest. tive demethylation and generate reactive oxygen species (ROS) This article is a PNAS Direct Submission. as by-products. Histone demethylases belong to two classes: This open access article is distributed under Creative Commons Attribution-NonCommercial- flavin adenine dinucleotide (FAD)-dependent monoamine oxi- NoDerivatives License 4.0 (CC BY-NC-ND). dases, the founding member being lysine-specific demethylase 1 1S.S. and H.W. contributed equally to this work. (LSD1/KDM1A), which generate hydrogen peroxide (H2O2), 2To whom correspondence may be addressed. Email: [email protected], mlhegde@ and jumonji (JMJ) family members, which generate superoxide houstonmethodist.org, or [email protected]. .– 2+ anion (O2 ) during Fe /O2-dependent oxidative decarboxyl- 3Present address: Texas Heart Institute, Houston, TX 77030. m ation of α-ketoglutarate (7–11). Demethylation of 5 C is carried 4Present address: School of Biomedical Informatics, The University of Texas Health Science out by ten-eleven translocation (TET) dioxygenases, which fol- Center, Houston, TX 77030. low the same reaction pathway as the JMJs and thus, generate First published August 21, 2020. www.pnas.org/cgi/doi/10.1073/pnas.1919445117 PNAS | September 8, 2020 | vol. 117 | no. 36 | 22183–22192 Downloaded by guest on September 25, 2021 These damages were repaired via the base excision repair are universal, although each ligand has distinct kinetics of DNA (BER)/single-strand break repair (SSBR) pathway (23). We damage induction and repair. documented the coordination of BER/SSBR with histone/CpG demethylation for promoter-specific repair of these damages dur- Generation of ROS due to Histone and CpG Demethylation and ing ligand-induced transcriptional activation, in contrast to what Induction of Oxidative Genome Damage during Gene Activation. we observed during ligand-independent gene activation via heat While the ligands used above all generate ROS in cells (27–31), shock (HS) when double-strand break repair (DSBR) was we selected RA for in-depth studies of demethylation-associated essential. oxidative genome damage and repair during gene activation. We used the RA-inducible retinoic acid receptor-β2 (RARβ2) gene Results activation in HEK293 cells as the model system. First, we con- Induction of Genome Damage in Diverse Gene Activation Systems. firmed RA-induced generation of ROS by fluorescence-activated ′ ′ An earlier study documented the generation of 8-oxoguanine (8- cell sorting (FACS) analysis of 2 ,7 -dihydrodichlorofluorescin A oxoG), the most abundant oxidized DNA base lesion, during diacetate (H2-DCFDA) oxidation (Fig. 2 ) and then showed the .– B activation of the B cell lymphoma 2 (BCL2) gene in MCF7 generation of both H2O2 and O2 by colorimetric assays (Fig. 2 C breast cancer line by 17β-estradiol (E2), a ligand for estrogen and ). Together, these observations suggest that RA-induced receptors (24). The formation of 8-oxoG was also observed global transcriptional reprogramming generates ROS, presum- during Myc-induced transcriptional activation (25). The authors ably because of histone/CpG demethylation. Using chromatin attributed G oxidation by ROS generated specifically during immunoprecipitation (ChIP) analysis, we then showed that RA oxidative demethylation of Lys9 methylated histone H3 in the reduced the Lys9 dimethylated H3 (H3K9me2) level in the RARβ2 promoter, which contains the retinoic acid response ele- gene promoters. On the basis of these observations, we postu- ment (RARE) (Fig. 2D). Similar reduction of the H3K9me2 level lated that diverse ligand-induced transcriptional reprogramming was not observed in a nonspecific region lacking RARE (Fig. 2D). involving the demethylation of histones and CpGs will cause Although we observed significant H3K9me2 demethylation not DNA base oxidation and strand break. The induction of genome before 60 min of RA treatment, the generation of global strand damage at a global scale followed by their repair can be moni- breaks, estimated
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