Highlights d A CRISPR screen for HDAC inhibitor sensitizers in DIPG identifies KDM1A (LSD1) d Corin, a dual inhibitor of LSD1 and HDACs, inhibits DIPG growth in vitro and in vivo d Corin alters histone modifications to promote differentiation and block cell cycle d A Corin-induced gene expression signature correlates with prolonged survival in DIPG

Background: Myocyte enhancer factor 2 (MEF2) proteins are essential for skeletal muscle development and regeneration, but their diverse roles in differentiation have not been defined. Results: Individual MEF2 proteins regulate distinct gene programs in skeletal muscle. Conclusion: Certain genes are preferentially sensitive to a specific MEF2 isoform. Significance: These findings provide opportunities to modulate MEF2 isoform-sensitive genes in skeletal muscle health and disease.

Histone modifications, largely regulated by histone acetyltransferases (HAT) and histone deacetylases, have been recognized as major regulatory mechanisms governing human diseases, including cancer. Despite significant effort and recent advances, the mechanism by which the HAT and transcriptional coactivator p300 mediates tumorigenesis remains unclear. Here, we use a genetic and chemical approach to identify the microphthalmia-associated transcription factor (MITF) as a critical downstream target of p300 driving human melanoma growth. Direct transcriptional control of MITF by p300-dependent histone acetylation within proximal gene regulatory regions was coupled to cellular proliferation, suggesting a significant growth regulatory axis. Further analysis revealed forkhead box M1 (FOXM1) as a key effector of the p300-MITF axis driving cell growth that is selectively activated in human melanomas. Targeted chemical inhibition of p300 acetyltransferase activity using a potent and selective catalytic p300/CBP inhibitor demonstrated significant growth inhibitory effects in melanoma cells expressing high levels of MITF. Collectively, these data confirm the critical role of the p300-MITF-FOXM1 axis in melanoma and support p300 as a promising novel epigenetic therapeutic target in human melanoma. Significance: These results show that MITF is a major downstream target of p300 in human melanoma whose expression is predictive of melanoma response to smallmolecule inhibition of p300 HAT activity.

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Background: Myocyte enhancer factor 2 (MEF2) proteins are key regulators of cardiac muscle differentiation and hypertrophy, but additional roles in this cell type have not been defined. Results: MEF2D regulates the cell cycle and survival of post-mitotic cardiomyocytes. Conclusion: MEF2D is required for proper neonatal cardiomyocyte homeostasis. Significance: These findings provide opportunities to modulate MEF2D activity in cardiomyocyte proliferation and survival.

The myocyte enhancer factor 2 (MEF2) transcription factor requires interactions with co-factors for precise regulation of its target genes. Our lab previously reported that the mammalian MEF2A isoform regulates the cardiomyocyte costamere, a critical muscle-specific focal adhesion complex involved in contractility, through its transcriptional control of genes encoding proteins localized to this cytoskeletal structure. To further dissect the transcriptional mechanisms of costamere gene regulation and identify potential co-regulators of MEF2A, a bioinformatics analysis of transcription factor binding sites was performed using the proximal promoter regions of selected costamere genes. One of these predicted sites belongs to the early growth response (EGR) transcription factor family. The EGR1 isoform has been shown to be involved in a number of pathways in cardiovascular homeostasis and disease, making it an intriguing candidate MEF2 coregulator to further characterize. Here, we demonstrate that EGR1 interacts with MEF2A and is a potent and specific repressor of MEF2 transcriptional activity. Furthermore, we show that costamere gene expression in cardiomyocytes is dependent on EGR1 transcriptional activity. This study identifies a mechanism by which MEF2 activity can be modulated to ensure that costamere gene expression is maintained at levels commensurate with cardiomyocyte contractile activity.

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