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Expression of the dermatomyositis autoantigen transcription intermediary factor 1? in regenerating muscle.

ABSTRACT: OBJECTIVE:Autoantibodies against transcription intermediary factor 1? (TIF1?) are found in many patients with dermatomyositis (DM). Although TIF1? is known to play a role in the differentiation of other tissues, its functional role in muscle regeneration has not been elucidated. This study was undertaken to explore the regulation and functional role of this protein during muscle differentiation and regeneration. METHODS:TIF1? expression was analyzed in human muscle biopsy specimens using immunofluorescence microscopy. Immunofluorescence microscopy and immunoblotting analyses were used to study TIF1? expression in a mouse model of muscle injury and repair. The effect of premature TIF1? silencing on muscle differentiation was studied in cultured mouse myoblasts. RESULTS:In muscle biopsy specimens from DM patients, TIF1? was expressed at low levels in the nuclei of histologically normal muscle cells but at high levels in the centralized nuclei of atrophic, perifascicular myofibers expressing markers of regeneration. TIF1? levels were also increased in regenerating myonuclei following muscle injury in mice. Premature silencing of TIF1? in vitro using small interfering RNA did not accelerate the expression of myogenin, a transcription factor that plays a central role in regulating relatively early stages of muscle differentiation. However, premature silencing of TIF1? did accelerate myotube fusion and the expression of myosin heavy chain (MyHC), a later marker of muscle differentiation. CONCLUSION:The DM autoantigen TIF1? is markedly up-regulated during muscle regeneration in human and mouse muscle cells. Premature silencing of this protein in cultured myoblasts accelerates MyHC expression and myoblast fusion. However, TIF1? may function independently of, or downstream from, myogenin.

SUBMITTER: Mohassel P

PROVIDER: S-EPMC4280343 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Expression of the dermatomyositis autoantigen transcription intermediary factor 1γ in regenerating muscle.

Mohassel Payam P Rosen Paul P Casciola-Rosen Livia L Pak Katherine K Mammen Andrew L AL

Arthritis & rheumatology (Hoboken, N.J.) 20150101 1

<h4>Objective</h4>Autoantibodies against transcription intermediary factor 1γ (TIF1γ) are found in many patients with dermatomyositis (DM). Although TIF1γ is known to play a role in the differentiation of other tissues, its functional role in muscle regeneration has not been elucidated. This study was undertaken to explore the regulation and functional role of this protein during muscle differentiation and regeneration.<h4>Methods</h4>TIF1γ expression was analyzed in human muscle biopsy specimen ...[more]

PMID: 25186009

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Project description:BackgroundStudies on amphibian limb regeneration began in the early 1700's but we still do not completely understand the cellular and molecular events of this unique process. Understanding a complex biological process such as limb regeneration is more complicated than the knowledge of the individual genes or proteins involved. Here we followed a systems biology approach in an effort to construct the networks and pathways of protein interactions involved in formation of the accumulation blastema in regenerating axolotl limbs.ResultsWe used the human orthologs of proteins previously identified by our research team as bait to identify the transcription factor (TF) pathways and networks that regulate blastema formation in amputated axolotl limbs. The five most connected factors, c-Myc, SP1, HNF4A, ESR1 and p53 regulate ~50% of the proteins in our data. Among these, c-Myc and SP1 regulate 36.2% of the proteins. c-Myc was the most highly connected TF (71 targets). Network analysis showed that TGF-?1 and fibronectin (FN) lead to the activation of these TFs. We found that other TFs known to be involved in epigenetic reprogramming, such as Klf4, Oct4, and Lin28 are also connected to c-Myc and SP1.ConclusionsOur study provides a systems biology approach to how different molecular entities inter-connect with each other during the formation of an accumulation blastema in regenerating axolotl limbs. This approach provides an in silico methodology to identify proteins that are not detected by experimental methods such as proteomics but are potentially important to blastema formation. We found that the TFs, c-Myc and SP1 and their target genes could potentially play a central role in limb regeneration. Systems biology has the potential to map out numerous other pathways that are crucial to blastema formation in regeneration-competent limbs, to compare these to the pathways that characterize regeneration-deficient limbs and finally, to identify stem cell markers in regeneration.

Dataset Information

Expression of the dermatomyositis autoantigen transcription intermediary factor 1? in regenerating muscle.

Publications

Expression of the dermatomyositis autoantigen transcription intermediary factor 1γ in regenerating muscle.

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