DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease

Magdy, Amal; Kim, Hee-Jin; Go, Hanyong; Lee, Jun Min; Sohn, Hyun Ahm; Haam, Keeok; Jung, Hyo-Jung; Park, Jong-Lyul; Yoo, Taekyeong; Kwon, Eun-Soo; Lee, Dong Hyeon; Choi, Murim; Kang, Keon Wook; Kim, Won; Kim, Mirang; ,

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Original Article

DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease

Amal Magdy^1,2, Hee-Jin Kim¹, Hanyong Go^1,2, Jun Min Lee^1,2, Hyun Ahm Sohn¹, Keeok Haam¹, Hyo-Jung Jung¹, Jong-Lyul Park^1,2, Taekyeong Yoo³, Eun-Soo Kwon^1,4, Dong Hyeon Lee⁵, Murim Choi³, Keon Wook Kang⁶, Won Kim⁵, Mirang Kim^1,2, on behalf of the Innovative Target Exploration of NAFLD (ITEN) Consortium

¹Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
²Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Republic of Korea
³Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
⁴Department of Biomolecular Science, KRIBB School of Bioscience, UST, Daejeon 34113, Korea
⁵Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul 07061, Republic of Korea
⁶College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea

Correspondence :

Won Kim ,
Tel: +82-2-870-2233, Fax: +82-2-831-2826, Email: drwon1@snu.ac.kr
Mirang Kim ,
Tel: +82-42-879-8113, Fax: +82-42-879-8119, Email: mirang@kribb.re.kr

Received: April 9, 2024 Revised: July 22, 2024 Accepted: July 24, 2024
*Amal Magdy and Hee-Jin Kim contributed equally to this work.

ABSTRACT

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.

KeyWords: MASLD; MASH; DNA methylation; Complement; Epigenetics