Genome-Scale CRISPR Knockout Screening Identifies BACH1 as a Key Regulator of Aflatoxin B<sub>1</sub>-Induced Oxidative Damage
Aflatoxin B<sub>1</sub> (AFB<sub>1</sub>) is amongst the mycotoxins commonly affecting human and animal health, raising global food safety and control concerns. The mechanisms underlying AFB<sub>1</sub> toxicity are poorly understood. Moreover, antidotes against A...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-09-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/9/1787 |
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| author | Jinfu Zhang Siyi Hu Changzhi Zhao Yuan Zhou Lu Zhang Hailong Liu Peng Zhou Sheng Li Liangliang Fu Zhuqing Zheng Yue Xiang Xuewen Xu Jinxue Ruan Xinyun Li Lvhui Sun Gang Cao Shuhong Zhao Xu Wang Shengsong Xie |
| author_facet | Jinfu Zhang Siyi Hu Changzhi Zhao Yuan Zhou Lu Zhang Hailong Liu Peng Zhou Sheng Li Liangliang Fu Zhuqing Zheng Yue Xiang Xuewen Xu Jinxue Ruan Xinyun Li Lvhui Sun Gang Cao Shuhong Zhao Xu Wang Shengsong Xie |
| author_sort | Jinfu Zhang |
| collection | DOAJ |
| description | Aflatoxin B<sub>1</sub> (AFB<sub>1</sub>) is amongst the mycotoxins commonly affecting human and animal health, raising global food safety and control concerns. The mechanisms underlying AFB<sub>1</sub> toxicity are poorly understood. Moreover, antidotes against AFB<sub>1</sub> are lacking. Genome-wide CRISPR/Cas9 knockout screening in porcine kidney cells identified the transcription factor BTB and CNC homolog 1 (BACH1) as a gene required for AFB<sub>1</sub> toxicity. The inhibition of BACH1 expression in porcine kidney cells and human hepatoma cells resulted in increased resistance to AFB<sub>1</sub>. BACH1 depletion attenuates AFB<sub>1</sub>-induced oxidative damage via the upregulation of antioxidant genes. Subsequently, virtual structural screening identified the small molecule 1-Piperazineethanol, α-[(1,3-benzodioxol-5-yloxy)methyl] -4-(2-methoxyphenyl) (M2) as an inhibitor of BACH1. M2 and its analogues inhibited AFB<sub>1</sub>-induced porcine and human cell death in vitro, while M2 administration significantly improved AFB<sub>1</sub>-induced symptoms of weight loss and liver injury in vivo. These findings demonstrate that BACH1 plays a central role in AFB<sub>1</sub>-induced oxidative damage by regulating antioxidant gene expression. We also present a potent candidate small-molecule inhibitor in developing novel treatments for AFB<sub>1</sub> toxicity. |
| first_indexed | 2024-03-10T00:53:24Z |
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| id | doaj.art-fbe1ebe0d5844450ae2c09e72da25a26 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T00:53:24Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-fbe1ebe0d5844450ae2c09e72da25a262023-11-23T14:48:56ZengMDPI AGAntioxidants2076-39212022-09-01119178710.3390/antiox11091787Genome-Scale CRISPR Knockout Screening Identifies BACH1 as a Key Regulator of Aflatoxin B<sub>1</sub>-Induced Oxidative DamageJinfu Zhang0Siyi Hu1Changzhi Zhao2Yuan Zhou3Lu Zhang4Hailong Liu5Peng Zhou6Sheng Li7Liangliang Fu8Zhuqing Zheng9Yue Xiang10Xuewen Xu11Jinxue Ruan12Xinyun Li13Lvhui Sun14Gang Cao15Shuhong Zhao16Xu Wang17Shengsong Xie18Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaNational Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaHubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, ChinaHubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaNational Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan 430070, ChinaKey Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education & Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs, Huazhong Agricultural University, Wuhan 430070, ChinaAflatoxin B<sub>1</sub> (AFB<sub>1</sub>) is amongst the mycotoxins commonly affecting human and animal health, raising global food safety and control concerns. The mechanisms underlying AFB<sub>1</sub> toxicity are poorly understood. Moreover, antidotes against AFB<sub>1</sub> are lacking. Genome-wide CRISPR/Cas9 knockout screening in porcine kidney cells identified the transcription factor BTB and CNC homolog 1 (BACH1) as a gene required for AFB<sub>1</sub> toxicity. The inhibition of BACH1 expression in porcine kidney cells and human hepatoma cells resulted in increased resistance to AFB<sub>1</sub>. BACH1 depletion attenuates AFB<sub>1</sub>-induced oxidative damage via the upregulation of antioxidant genes. Subsequently, virtual structural screening identified the small molecule 1-Piperazineethanol, α-[(1,3-benzodioxol-5-yloxy)methyl] -4-(2-methoxyphenyl) (M2) as an inhibitor of BACH1. M2 and its analogues inhibited AFB<sub>1</sub>-induced porcine and human cell death in vitro, while M2 administration significantly improved AFB<sub>1</sub>-induced symptoms of weight loss and liver injury in vivo. These findings demonstrate that BACH1 plays a central role in AFB<sub>1</sub>-induced oxidative damage by regulating antioxidant gene expression. We also present a potent candidate small-molecule inhibitor in developing novel treatments for AFB<sub>1</sub> toxicity.https://www.mdpi.com/2076-3921/11/9/1787AFB<sub>1</sub>BACH1CRISPR screeninginhibitor |
| spellingShingle | Jinfu Zhang Siyi Hu Changzhi Zhao Yuan Zhou Lu Zhang Hailong Liu Peng Zhou Sheng Li Liangliang Fu Zhuqing Zheng Yue Xiang Xuewen Xu Jinxue Ruan Xinyun Li Lvhui Sun Gang Cao Shuhong Zhao Xu Wang Shengsong Xie Genome-Scale CRISPR Knockout Screening Identifies BACH1 as a Key Regulator of Aflatoxin B<sub>1</sub>-Induced Oxidative Damage Antioxidants AFB<sub>1</sub> BACH1 CRISPR screening inhibitor |
| title | Genome-Scale CRISPR Knockout Screening Identifies BACH1 as a Key Regulator of Aflatoxin B<sub>1</sub>-Induced Oxidative Damage |
| title_full | Genome-Scale CRISPR Knockout Screening Identifies BACH1 as a Key Regulator of Aflatoxin B<sub>1</sub>-Induced Oxidative Damage |
| title_fullStr | Genome-Scale CRISPR Knockout Screening Identifies BACH1 as a Key Regulator of Aflatoxin B<sub>1</sub>-Induced Oxidative Damage |
| title_full_unstemmed | Genome-Scale CRISPR Knockout Screening Identifies BACH1 as a Key Regulator of Aflatoxin B<sub>1</sub>-Induced Oxidative Damage |
| title_short | Genome-Scale CRISPR Knockout Screening Identifies BACH1 as a Key Regulator of Aflatoxin B<sub>1</sub>-Induced Oxidative Damage |
| title_sort | genome scale crispr knockout screening identifies bach1 as a key regulator of aflatoxin b sub 1 sub induced oxidative damage |
| topic | AFB<sub>1</sub> BACH1 CRISPR screening inhibitor |
| url | https://www.mdpi.com/2076-3921/11/9/1787 |
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