Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1

Fukumoto, Aono; Yamanaka, Tomoki; Yanaizu, Motoaki; Nakamori, Masayuki; Hama, Manami; Yasumizu, Yoshiaki; Shiotsu, Kana; Matsumura, Tsuyoshi; Nutter, Curtis A.; Kubota, Tomoya; Fujimura, Harutoshi; Kino, Yoshihiro; Swanson, Maurice S.; Inoue, Kimiko; Takahashi, Masanori P.

doi:https://doi.org/10.1093/hmg/ddaf124

Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1

Fukumoto, Aono; Yamanaka, Tomoki; Yanaizu, Motoaki et al.

Human Molecular Genetics, 2025, 34(20), 1718-1732

Number of Access:689（2026-04-05 10:36 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/103068

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Title	Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1
Creator	CreatorName Fukumoto, Aono
	CreatorName Yamanaka, Tomoki
	NRID 1000020913362 1000020913362 CreatorName Yanaizu, Motoaki
	NRID 1000060630233 1000060630233 ORCID 0000-0003-4714-3044 0000-0003-4714-3044 researchmap permalink mnakamori mnakamori Scopus Author ID 7005463823 7005463823 CreatorName Nakamori, Masayuki
	CreatorName Hama, Manami
	ORCID 0000-0002-9872-4909 0000-0002-9872-4909 researchmap permalink yyasumizu yyasumizu Scopus Author ID 57204510528 57204510528 CreatorName Yasumizu, Yoshiaki
	CreatorName Shiotsu, Kana
	NRID 1000030549366 1000030549366 CreatorName Matsumura, Tsuyoshi
	CreatorName Nutter, Curtis A.
	NRID 1000020573231 1000020573231 ORCID 0000-0003-1004-8537 0000-0003-1004-8537 researchmap permalink n-phys n-phys Scopus Author ID 26633163700 26633163700 CreatorName Kubota, Tomoya
	NRID 1000020263246 1000020263246 CreatorName Fujimura, Harutoshi
	NRID 1000080415140 1000080415140 CreatorName Kino, Yoshihiro
	CreatorName Swanson, Maurice S.
	CreatorName Inoue, Kimiko
	NRID 1000020359847 1000020359847 ORCID 0000-0002-5513-5012 0000-0002-5513-5012 researchmap permalink mtakahas mtakahas Scopus Author ID 15038719500 15038719500 CreatorName Takahashi, Masanori P.
Subject	liver
	MBNL
	mouse
	mRNA
	myotonic dystrophy
Description	This is a pre-copyedited, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Fukumoto A., Yamanaka T., Yanaizu M., et al., Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1, Human Molecular Genetics 34(20), 1718 (2025), https://doi.org/10.1093/hmg/ddaf124 is available online at: https://doi.org/10.1093/hmg/ddaf124.
Abstract	Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the DMPK 3′-untranslated region, affecting multiple organs, including the skeletal muscles, eyes, heart, central nervous system, and endocrine system. A major pathogenic event in DM1 is the sequestration of muscleblind-like (MBNL) proteins by CUG repeat-containing RNAs transcribed from expanded repeats. Among the various symptoms of DM1, lipid abnormalities and liver dysfunction are frequent but remain understudied. Although abnormal splicing of insulin receptor RNA is implicated, it cannot fully explain these abnormalities. To investigate the molecular mechanisms, we performed transcriptome analysis of postmortem livers from patients with DM1 and Mbnl-knockout mice. RNA-sequencing revealed differentially expressed genes (DEGs) and aberrant splicing in DM1 livers. A comparison of Mbnl1- and Mbnl2-knockout mouse livers indicated that MBNL1 accounts for some of the transcriptomic changes observed in patients with DM1. The DEGs included those related to lipid metabolism and liver fibrosis. DM1-associated changes in the liver transcriptome partially resolved sexual dimorphism in gene expression and uncovered distinct sex-specific pathway alterations. Besides the known MBNL-regulated genes, those related to lipid and glucose metabolism were identified in the aberrant splicing clusters detected in DM1. A correlation between serum gamma-glutamyl transferase levels and overall splicing abnormalities was observed, linking splicing changes in the liver to clinical abnormalities. These findings provide new insights into the molecular basis of DM1-related metabolic and hepatic abnormalities, enhancing our understanding of the systemic effects of this disease.
Publisher	Oxford University Press
Source Title	Human Molecular Genetics
Volume (Issue)	34(20)
Page	1718-1732
Date of Issued	2025-08-13
Language	English
Handle URL	https://hdl.handle.net/11094/103068
PISSN	09646906
eISSN	14602083
Relation.isVersionOf	DOI (Publisher Version) https://doi.org/10.1093/hmg/ddaf124
Access Rights	embargoed access
CopyRight	The full-text file will be made open to the public on 13 August 2026 in accordance with the publisher's policy.
oaire:version	Accepted Manuscript
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Human Molecular Genetics. 2025, 34(20), p. 1718-1732
DC.title	Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1
DC.creator	Fukumoto, Aono
	Yamanaka, Tomoki
	Yanaizu, Motoaki
	Nakamori, Masayuki
	Hama, Manami
	Yasumizu, Yoshiaki
	Shiotsu, Kana
	Matsumura, Tsuyoshi
	Nutter, Curtis A.
	Kubota, Tomoya
	Fujimura, Harutoshi
	Kino, Yoshihiro
	Swanson, Maurice S.
	Inoue, Kimiko
	Takahashi, Masanori P.
DC.publisher	Oxford University Press
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-08-13
DC.identifier	https://doi.org/10.1093/hmg/ddaf124
DC.subject	liver
	MBNL
	mouse
	mRNA
	myotonic dystrophy
DC.description	This is a pre-copyedited, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Fukumoto A., Yamanaka T., Yanaizu M., et al., Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1, Human Molecular Genetics 34(20), 1718 (2025), https://doi.org/10.1093/hmg/ddaf124 is available online at: https://doi.org/10.1093/hmg/ddaf124.
DCTERMS.abstract	Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the DMPK 3′-untranslated region, affecting multiple organs, including the skeletal muscles, eyes, heart, central nervous system, and endocrine system. A major pathogenic event in DM1 is the sequestration of muscleblind-like (MBNL) proteins by CUG repeat-containing RNAs transcribed from expanded repeats. Among the various symptoms of DM1, lipid abnormalities and liver dysfunction are frequent but remain understudied. Although abnormal splicing of insulin receptor RNA is implicated, it cannot fully explain these abnormalities. To investigate the molecular mechanisms, we performed transcriptome analysis of postmortem livers from patients with DM1 and Mbnl-knockout mice. RNA-sequencing revealed differentially expressed genes (DEGs) and aberrant splicing in DM1 livers. A comparison of Mbnl1- and Mbnl2-knockout mouse livers indicated that MBNL1 accounts for some of the transcriptomic changes observed in patients with DM1. The DEGs included those related to lipid metabolism and liver fibrosis. DM1-associated changes in the liver transcriptome partially resolved sexual dimorphism in gene expression and uncovered distinct sex-specific pathway alterations. Besides the known MBNL-regulated genes, those related to lipid and glucose metabolism were identified in the aberrant splicing clusters detected in DM1. A correlation between serum gamma-glutamyl transferase levels and overall splicing abnormalities was observed, linking splicing changes in the liver to clinical abnormalities. These findings provide new insights into the molecular basis of DM1-related metabolic and hepatic abnormalities, enhancing our understanding of the systemic effects of this disease.
DC.rights	The full-text file will be made open to the public on 13 August 2026 in accordance with the publisher's policy.
DC.format	103068
citation_title	Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1
citation_author	Fukumoto, Aono
	Yamanaka, Tomoki
	Yanaizu, Motoaki
	Nakamori, Masayuki
	Hama, Manami
	Yasumizu, Yoshiaki
	Shiotsu, Kana
	Matsumura, Tsuyoshi
	Nutter, Curtis A.
	Kubota, Tomoya
	Fujimura, Harutoshi
	Kino, Yoshihiro
	Swanson, Maurice S.
	Inoue, Kimiko
	Takahashi, Masanori P.
citation_publisher	Oxford University Press
citation_language	English
citation_date	2025-08-13
citation_journal_title	Human Molecular Genetics
citation_volume	34
citation_issue	20
citation_firstpage	1718
citation_lastpage	1732
citation_doi	https://doi.org/10.1093/hmg/ddaf124
citation_public_url	https://hdl.handle.net/11094/103068

Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1

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