DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease
Background/Aims Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction–associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the pot...
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| Format: | Article |
| Language: | English |
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Korean Association for the Study of the Liver
2024-10-01
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| Series: | Clinical and Molecular Hepatology |
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| Online Access: | http://e-cmh.org/upload/pdf/cmh-2024-0229.pdf |
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| author | Amal Magdy Hee-Jin Kim Hanyong Go Jun Min Lee Hyun Ahm Sohn Keeok Haam Hyo-Jung Jung Jong-Lyul Park Taekyeong Yoo Eun-Soo Kwon Dong Hyeon Lee Murim Choi Keon Wook Kang Won Kim Mirang Kim on behalf of the Innovative Target Exploration of NAFLD (ITEN) Consortium |
| author_facet | Amal Magdy Hee-Jin Kim Hanyong Go Jun Min Lee Hyun Ahm Sohn Keeok Haam Hyo-Jung Jung Jong-Lyul Park Taekyeong Yoo Eun-Soo Kwon Dong Hyeon Lee Murim Choi Keon Wook Kang Won Kim Mirang Kim on behalf of the Innovative Target Exploration of NAFLD (ITEN) Consortium |
| author_sort | Amal Magdy |
| collection | DOAJ |
| description | Background/Aims Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction–associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD. Methods Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction–associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing. Results Methylome and transcriptome analyses of liver biopsies revealed significant (P<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA, and SERPING1, as well as hypomethylation (P<0.0005) and upregulation (P<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data. Conclusions Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD. |
| format | Article |
| id | doaj-art-f8340be6f5b64e369efda5e29efcbe27 |
| institution | Kabale University |
| issn | 2287-2728 2287-285X |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Korean Association for the Study of the Liver |
| record_format | Article |
| series | Clinical and Molecular Hepatology |
| spelling | doaj-art-f8340be6f5b64e369efda5e29efcbe272024-11-19T00:30:15ZengKorean Association for the Study of the LiverClinical and Molecular Hepatology2287-27282287-285X2024-10-0130482484410.3350/cmh.2024.02291982DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver diseaseAmal Magdy0Hee-Jin Kim1Hanyong Go2Jun Min Lee3Hyun Ahm Sohn4Keeok Haam5Hyo-Jung Jung6Jong-Lyul Park7Taekyeong Yoo8Eun-Soo Kwon9Dong Hyeon Lee10Murim Choi11Keon Wook Kang12Won Kim13Mirang Kim14on behalf of the Innovative Target Exploration of NAFLD (ITEN) Consortium Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, KoreaBackground/Aims Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction–associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD. Methods Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction–associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing. Results Methylome and transcriptome analyses of liver biopsies revealed significant (P<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA, and SERPING1, as well as hypomethylation (P<0.0005) and upregulation (P<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data. Conclusions Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.http://e-cmh.org/upload/pdf/cmh-2024-0229.pdfmasldmashdna methylationcomplementepigenetics |
| spellingShingle | Amal Magdy Hee-Jin Kim Hanyong Go Jun Min Lee Hyun Ahm Sohn Keeok Haam Hyo-Jung Jung Jong-Lyul Park Taekyeong Yoo Eun-Soo Kwon Dong Hyeon Lee Murim Choi Keon Wook Kang Won Kim Mirang Kim on behalf of the Innovative Target Exploration of NAFLD (ITEN) Consortium DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease Clinical and Molecular Hepatology masld mash dna methylation complement epigenetics |
| title | DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease |
| title_full | DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease |
| title_fullStr | DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease |
| title_full_unstemmed | DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease |
| title_short | DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease |
| title_sort | dna methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction associated steatotic liver disease |
| topic | masld mash dna methylation complement epigenetics |
| url | http://e-cmh.org/upload/pdf/cmh-2024-0229.pdf |
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