Homo-trimerization is essential for the transcription factor function of Myrf for oligodendrocyte differentiation

Kim, Dongkyeong; Choi, Jinok; Fan, Chuandong; Shearer, Randall S.; Sharif, Mohamed; Busch, Patrick; Park, Yungki

doi:10.1093/nar/gkx080

Cited by 45 publications

(86 citation statements)

References 30 publications

(77 reference statements)

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“…To test this hypothesis, we performed a luciferase assay in Oli-neu cells with Rffl. Rffl is a well-characterized Myrf luciferase reporter 5,21,29 , which was generated by cloning a Myrf ChIP-seq peak in the Rffl locus (rn4 chr10:71034166-71034749) into pGL3-promoter. Flag-Myrf significantly elevated the reporter activity of Rffl, as reported before 5,21,29 .…”

Section: Resultsmentioning

confidence: 99%

“…The core biochemical activity of the ICA homo-trimer -inducing homo-trimerization by triple β-helix and subsequently performing auto-cleavage -is conserved from human to virus 4,5,[20][21][22][23] and allows Myrf to work as a membrane-bound transcription factor. If deleterious mutations hit the ICA domain, its auto-cleavage function may be impaired, potentially abolishing the transcription factor function of Myrf.…”

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confidence: 99%

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Functional mechanism and pathogenic potential of MYRF ICA domain mutations implicated in birth defects

Fan

Sharif

et al. 2020

Sci Rep

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Myrf is a membrane-bound transcription factor that plays a key role in various biological processes. the intramolecular chaperone Auto-processing (icA) domain of Myrf forms a homo-trimer, which carries out the auto-cleavage of Myrf. the icA homo-trimer-mediated auto-cleavage of Myrf is a prerequisite for its transcription factor function in the nucleus. Recent exome sequencing studies have implicated two MYRF ICA domain mutations (V679A and R695H) in a novel syndromic form of birth defects. It remains unknown whether and how the two mutations impact the transcription factor function of Myrf and, more importantly, how they are pathogenic for congenital anomalies. Here, we show that V679A and R695H cripple the ICA domain, blocking the auto-cleavage of Myrf. Consequently, Myrf-V679A and Myrf-R695H do not exhibit any transcriptional activity. Molecular modeling suggests that V679A and R695H abrogate the auto-cleavage function of the ICA homo-trimer by destabilizing its homo-trimeric assembly. We also found that the ICA homo-trimer can tolerate one copy of Myrf-V679A or Myrf-R695H for its auto-cleavage function, indicating that V679A and R695H are not dominant negatives. Thus, if V679A and R695H in a heterozygous state caused birth defects, it would be via haploinsufficiency of MYRF.Myrf (myelin regulatory factor, previously known as C11orf9 [the human gene] and Mrf [the mouse gene]) is a pleiotropic membrane-bound transcription factor 1-7 . Throughout this paper, MYRF and Myrf refer to the human and mouse genes, respectively. In the murine central nervous system (CNS), Myrf is specifically expressed by oligodendrocytes (OLs) 1,8 . Conditional knockout of Myrf in OL lineage cells led to widespread dysmyelination and severe neurological deficits 1 . Myrf is also indispensable for the life-long maintenance, plasticity, and regeneration of CNS myelin 9-11 . These studies left the impression that Myrf is a "myelin" transcription factor, and hence the name Myrf. We now know that MYRF is also expressed in other tissues such as stomach, lung, heart, ovary, eye, and developing gonads [12][13][14][15] . Consistently, MYRF coding variants have been implicated in both myelin and non-myelin diseases [13][14][15][16][17][18][19] , and whole-body Myrf knockout led to embryonic lethality in mouse independent of OL development 1 . In keeping with myelin-independent functions of Myrf, Myrf orthologs are found and play an important role in organisms without myelin 2,3,6,7 .Myrf is generated as a type-II membrane protein in the endoplasmic reticulum (ER) 4-6 . The Intramolecular Chaperone Auto-processing (ICA) domain is pivotal to the auto-cleavage of Myrf 4,5,20 . The ICA domain forms a homo-trimer, which as an intramolecular chaperone helps Myrf to form a homo-trimer in the ER membrane by chaperoning the formation of a triple β-helix (the intramolecular chaperone function, Fig. 1) 4,5,20-23 . As soon as the triple β-helix is completed, the ICA homo-trimer performs the auto-cleavage reactions that cleave the three P586-S587 peptide bon...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Functional mechanism and pathogenic potential of MYRF ICA domain mutations implicated in birth defects

Fan

Sharif

et al. 2020

Sci Rep

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“…MYRF is a membrane-associated transcription factor that is activated through autocatalytic cleavage via the peptidase S74 domain to bind the enhancer region of target genes (Bujalka et al, 2013). It functions as a homotrimer in vivo in the nucleus to perform its role in transcription (Kim et al, 2017). Autoprocessing is apparently constitutive and is essential for transcriptional activity.…”

Section: | Discussionmentioning

confidence: 99%

De novo variants in Myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies

Pinz

Pyle

et al. 2018

American J of Med Genetics Pt A

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Myelin Regulatory Factor (MYRF) is a transcription factor that has previously been associated with the control of the expression of myelin-related genes. However, it is highly expressed in human tissues and mouse embryonic tissues outside the nervous system such as the stomach, lung, and small intestine. It has not previously been reported as a cause of any Mendelian disease. We report here two males with Scimitar syndrome [MIM 106700], and other features including penoscrotal hypospadias, cryptorchidism, pulmonary hypoplasia, tracheal anomalies, congenital diaphragmatic hernia, cleft spleen, thymic involution, and thyroid fibrosis. Gross neurologic functioning appears to be within normal limits. In both individuals a de novo variant in MYRF was identified using exome sequencing. Neither variant is found in gnomAD. Heterozygous variants in MYRF should be considered in patients with variants of Scimitar syndrome and urogenital anomalies.

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“…The other two D-mis variants (p.V679R and p.R695H) are located in the intramolecular chaperone auto-processing domain (ICD) in a leucine zipper 29 . Mutations in the leucine zipper of the ICD domain may inhibit the trimerization of MYRF, resulting in the failure of formation of the N-terminal trimer 29 which is important for the transcription factor function 30 . MYRF is thought to be an essential transcription factor for oligodendrocyte differentiation and myelination 31 .…”

Section: Characteristicsmentioning

confidence: 99%

Genetic analysis ofde novovariants reveals sex differences in complex and isolated congenital diaphragmatic hernia and indicatesMYRFas a candidate gene

Zhou

et al. 2017

Preprint

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Homo-trimerization is essential for the transcription factor function of Myrf for oligodendrocyte differentiation

Cited by 45 publications

References 30 publications

Functional mechanism and pathogenic potential of MYRF ICA domain mutations implicated in birth defects

Functional mechanism and pathogenic potential of MYRF ICA domain mutations implicated in birth defects

De novo variants in Myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies

Genetic analysis ofde novovariants reveals sex differences in complex and isolated congenital diaphragmatic hernia and indicatesMYRFas a candidate gene

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