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HomeCirculation ResearchVol. 127, No. 9In This Issue Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessResearch ArticlePDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published8 Oct 2020https://doi.org/10.1161/RES.0000000000000443Circulation Research. 2020;127:1119is related toEpigenomic and Transcriptomic Dynamics During Human Heart OrganogenesisEnhancement of ALK1 Signaling as a HHT Therapy (p 1122)Boosting activity of kinase ALK1 could be a treatment for hereditary hemorrhagic telangiectasia, say Kim et al.Download figureDownload PowerPointHereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by vascular abnormalities called arteriovenous malformations (AVMs) in which arteries are directly connected to veins. Without intervening capillaries, blood pressure in the veins becomes excessive and can cause aneurysms and ruptures. Indeed, HHT patients often endure frequent bleeds and anemia, and sometimes suffer more severe events such as brain or pulmonary hemorrhages. HHT is caused by mutations in one of three genes—ALK1, ENG, or SMAD4—all of which encode components of a TGFβ-related growth factor signaling pathway. Because ninety percent of HHT cases are driven by ALK1 or ENG mutations, Kim et al focused on these two factors, examining how they might interact and compensate for each other. Using mice that conditionally lacked either ALK1 or ENG and had AVMs as a result, the team found that genetically increasing ALK1 production could prevent AVMs in the ENG- and ALK-lacking mice, but that increasing ENG production could only compensate for deficiency of ENG, not ALK1. Together these results suggest that ALK1 acts downstream of ENG in their shared signaling pathway and that augmenting ALK1 production could be a therapeutic approach for treating HHT.Periostin Is a Target to Treat PH (p 1138)Nie et al suggest periostin as a novel therapeutic target for treating pulmonary hypertension.Download figureDownload PowerPointPulmonary hypertension (PH) is a life threatening disease in which excess proliferation of vascular smooth muscle cells (VSMCs) and deposition of extracellular matrix (ECM) thickens the walls of the lung vasculature causing an increase in pulmonary blood pressure. Vasodilatory medications are used to treat the symptoms of the disease, but there are no available treatments that target the underlying pathologic remodeling. Nie and colleagues now suggest that drugs targeting the secreted ECM protein periostin might work. Periostin is unusually abundant in the arteries of PH patients’ lungs and is thought to be involved in cell adhesion and wound healing mechanisms such as proliferation and migration of VSMCs. The team has now confirmed the increased production of periostin in patient lungs and shown the same is true for mice with induced PH. Moreover they showed that genetic deletion of periostin attenuated PH in mice, while suppression of periostin via RNA inhibition could even reverse pathologic vessel thickening and right ventricle hypertrophy. The team went on to identify factors—HIF-1A and TrkB—that mediate periostin’s effects in cultured arterial cells, and suggest that blocking either these factors or periostin itself could be novel strategies for treating PH.Gene Regulatory Dynamics of Developing Human Heart (p e184)VanOudenhove et al examine the epigenomics and transcriptomics of the developing human heart.Download figureDownload PowerPointCongenital heart defects (CHDs) are a common form of birth abnormality. While some genes have been linked to CHDs, the majority—nearly sixty percent—have unknown etiologies. It’s thought that multiple genetic and environmental factors contribute to CHDs, one of which could be variations in regulatory regions of the genome. To find such heart-specific regulatory regions, VanOudenhove and colleagues examined heart tissue from human embryos obtained 4 to 8 weeks after conception. They performed chromatin immunoprecipitation (ChIP) experiments to scour the heart genomes for histone modifications associated with increased or decreased gene transcription. They also performed transcriptome analysis to see whether the genomic regions identified by ChIP corresponded with the activity status of nearby genes. In total, the team found more than 12 thousand previously unknown enhancers that were enriched for binding sites for heart-specific transcription factors (including GATA, MEF2 and NKX) and that tended to be close to genes activated in the heart. Many of the regions also contained sequence variations previously associated with atrial fibrillation. These newly identified sites are potential CHD candidate loci, say the authors, who have made their data freely available for study. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesEpigenomic and Transcriptomic Dynamics During Human Heart OrganogenesisJennifer VanOudenhove, et al. Circulation Research. 2020;127:e184-e209 October 9, 2020Vol 127, Issue 9Article InformationMetrics Download: 270 © 2020 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000443 Originally publishedOctober 8, 2020 PDF download