Background: How BAF250a regulates nucleosome configuration in ES cells is not clear. Results: BAF250a regulates nucleosome occupancy and H3K27me3 to control gene expression during ES cell differentiation. Conclusion: BAF250a plays a key role in poised chromatin regulation. Significance: Understanding the mechanisms of chromatin remodeling in poised chromatin regulation provides epigenetic insights into ES cell differentiation.

Type I interferons (IFNs) stimulate transcription through a latent heterotrimeric transcription factor composed of tyrosinephosphorylated STAT1 and STAT2 and the DNA binding partner IRF9, with STAT2 contributing a critical transactivation domain. Human RVB1 and RVB2, which are highly conserved AAA ؉ ATP binding proteins contained in chromatin-remodeling complexes such as Ino80, SNF2-related CBP activator protein (SRCAP), and Tip60/NuA4, interacted with the transactivation domain of STAT2 in the nuclei of IFN-stimulated cells. RNA interference (RNAi) experiments demonstrated that RVB proteins were required for robust activation of IFN-␣-stimulated genes (ISGs). The requirement for RVB proteins was specific to IFN-␣/ STAT2 signaling; transcription of tumor necrosis factor alpha (TNF-␣)-and IFN-␥-driven genes was not affected by RVB1 depletion. Using RNAi-based depletion, we assessed the involvement of catalytic subunits of the RVB-containing Tip60, BRD8, Ino80, SRCAP, and URI complexes. No component other than RVB1/2 was uniquely required for ISG induction, suggesting that RVB1/2 functions as part of an as yet unidentified complex. Chromatin immunoprecipitation assays indicated that RVB1/2 was required for recruitment of RNA polymerase II (Pol II) to ISG promoters but was dispensable for STAT2 recruitment to chromatin. We hypothesize that an RVB1/2 chromatin-remodeling complex is required for efficient Pol II recruitment and initiation at ISG promoters and is recruited through interaction with the STAT2 transactivation domain. Interferons (IFNs) are a family of pleiotropic cytokines primarily known for their ability to establish a potent antiviral state via modulation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signal transduction pathway. Alternatively, aberrant production of IFNs correlates with systemic autoimmunity, underscoring the importance of the stringent regulation of IFN responses. Type I IFNs activate the heterotrimeric transcription factor ISGF3, composed of tyrosine-phosphorylated STAT1 and STAT2 and an auxiliary DNA binding protein, IRF9. Following IFN stimulation, phosphorylated ISGF3 translocates into the nucleus, binds the interferon-stimulated response elements (ISREs) in the promoters of IFN-␣/␤-stimulated genes (ISGs), and rapidly and robustly induces the transcription of a large family of previously silent genes. ISGs subsequently influence multiple cellular pathways involved in innate immunity in order to protect against viral and bacterial replication, including modulation of cell stress responses, apoptosis, proliferation, translation, and innate and adaptive immune signaling (1). In the context of ISGF3, STAT2 contains an essential transactivation domain (TAD) that provides most of the transcriptional function to the transcription factor complex, whereas STAT1 and IRF9 confer DNA sequence specificity (2). Induction of IFN target genes provides a robust system for studying the molecular mechanisms underlying transcriptional regulation. However, little is...

Generation of induced cardiomyocytes (iCMs) directly from fibroblasts offers a great opportunity for cardiac disease modeling and cardiac regeneration. A major challenge of iCM generation is the low conversion rate. To address this issue, we attempted to identify small molecules that could potentiate the reprogramming ability towards cardiac fate by removing inhibitory roadblocks. Using mouse embryonic fibroblasts as the starting cell source, we first screened 47 cardiac development related epigenetic and transcription factors, and identified an unexpected role of H3K4 methyltransferase Mll1 and related factor Men1 in inhibiting iCM reprogramming. We then applied small molecules (MM408 and MI503) of Mll1 pathway inhibitors and observed an improved efficiency in converting embryonic fibroblasts and cardiac fibroblasts into functional cardiomyocyte-like cells. We further observed that these inhibitors directly suppressed the expression of Mll1 target gene Ebf1 involved in adipocyte differentiation. Consequently, Mll1 inhibition significantly decreased the formation of adipocytes during iCM induction. Therefore, Mll1 inhibitors likely increased iCM efficiency by suppressing alternative lineage gene expression. Our studies show that targeting Mll1 dependent H3K4 methyltransferase activity provides specificity in the process of cardiac reprogramming. These findings shed new light on the molecular mechanisms underlying cardiac conversion of fibroblasts and provide novel targets and small molecules to improve iCM reprogramming for clinical applications.

Myocardial infarction (MI) is the leading cause of death worldwide. Recent advances in stem cell research hold great potential for heart tissue regeneration through stem cell-based therapy. While multiple cell types have been transplanted into MI heart in preclinical studies or clinical trials, reduction of scar tissue and restoration of cardiac function have been modest. Several challenges hamper the development and application of stem cell-based therapy for heart regeneration. Application of cardiac progenitor cells (CPCs) and cardiac tissue engineering for cell therapy has shown great promise to repair damaged heart tissue. This review presents an overview of the current applications of embryonic CPCs and the development of cardiac tissue engineering in regeneration of functional cardiac tissue and reduction of side effects for heart regeneration. We aim to highlight the benefits of the cell therapy by application of CPCs and cardiac tissue engineering during heart regeneration.

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