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Engineering a superactivator of smooth muscle gene expression with the Myocardin condensate forming region [ChIP-seq]

ABSTRACT: Differentiation of smooth muscle cells (SMCs) is accompanied by the expression of a battery of genes controlled by serum response factor (SRF), a ubiquitous transcription factor with weak intrinsic transcriptional activity. Myocardin (MYOCD) is a potent transcriptional coactivator that activates smooth muscle differentiation through its association with SRF. MYOCD forms condensates through its highly disordered transcription activation domain (TAD), whereas SRF displays a diffuse distribution within the nucleus. SRF is recruited to nuclear condensates by the TAD of MYOCD (MYOCD-TAD), thereby triggering the smooth muscle gene program. Swapping the weak TAD of SRF with that of MYOCD enables SRF to form condensates and acquire the ability to reprogram fibroblasts to SMCs. SRF-MYOCD-TAD chimeric protein exhibits stronger transcriptional activity on smooth muscle genes than MYOCD. Using protein proximity labelling, quantitative proteomics and super-resolution confocal microscopy, we show that MYOCD-TAD condensates aggregate chromatin remodelers, RNA polymerases, and mRNA processing factors to drive smooth muscle gene expression. These findings provide insights into the mechanisms whereby nuclear condensates promote tissue-specific gene expression and point toward a strategy for engineering superactivators leveraging transcriptional condensates.

ORGANISM(S): Mus musculus

PROVIDER: GSE294913 | GEO | 2025/09/02

REPOSITORIES: GEO

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Project description:Smooth muscle cells (SMCs) display dynamic plasticity by changing phenotype under various pathophysiological conditions. Uncovering how SMCs regulate their phenotype is a key to understanding the molecular mechanisms of a number of gastrointestinal diseases. MicroRNAs (miRNAs), generated in cells by Dicer, have been identified as regulators of the differentiation state of SMCs. The goal of this study was to investigate the role of miRNAs during the development of gastrointestinal SMCs in a transgenic animal model. We generated SMC-specific Dicer (smDicer) null animals that express the reporter, green fluorescence protein (eGFP), in a SMC-specific manner. eGFP labeled SMCs were used for morphological, cytometric and genetic studies of smDicer null mutant and wild type control mice. The structure of the bowel wall was examined by confocal microscopy, and function was evaluated by recording spontaneous and evoked contractions. SMCs were purified with fluorescence-activated cell sorting and SM specific gene expression studies were performed with genechip arrays, PCR and quantitative PCR. Bioinformatic analyses were used to characterize the interaction between miRNAs and target genes. SMC-specific knockout of Dicer prevented SMC miRNA biogenesis, causing dramatic changes in phenotype, function, and global gene expression in SMCs. Profiling and bioinformatic analyses showed SMC phenotype is regulated by a complex network of positive and negative feedback by SM miRNAs, serum response factor (SRF), and other transcriptional factors. SM miRNAs play an important role in growth, development and survival of SMCs. Phenotypic changes of SMCs may be regulated through multiple pathways in an interaction network of SM miRNAs, SRF, and additional transcriptional factors. We used microarrays to identify genetic changes during the development of gastric smooth muscle cells in the smDicer null mice. Mouse mRNA microarrays were performed on GeneChipÂ® Mouse Genome 430 2.0 Arrays (Affymetrix). Total RNAs isolated from the jejunal muscularis of the smDicer knockout (KO) and the wild type (WT) control mice at the ages of ~3 weeks were used for the arrays. The cDNA synthesis, hybridization, cDNA labeling, and scanning were performed. Gene expression between the smDicer KO and the WT controls were compared.

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Engineering a superactivator of smooth muscle gene expression with the Myocardin condensate forming region [ChIP-seq]

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