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Huang, H.-Y. S.

Publications and source records attributed to Huang, H.-Y. S..

2 recordsLinked to original sources

Localization of the pioneer factor GAF to subnuclear foci is driven by DNA binding and required to silence satellite repeat expression

Abstract/SummaryThe eukaryotic genome is organized to enable the precise regulation of gene expression required for development. This organization is established during early development when the embryo transitions from a fertilized germ cell to the totipotent zygote. To understand the factors and processes that drive genomic organization, we focused on the pioneer factor GAGA factor (GAF) that is required for early embryonic development in Drosophila. GAF transcriptionally activates the zygotic genome and is localized to subnuclear foci. We show that this non-uniform distribution is driven by binding to the highly abundant GA-satellite repeats. At GA-repeats, GAF is necessary to form heterochromatin and silence transcription. Thus, GAF is required to establish both active and silent regions. We propose that foci formation enables GAF to have opposing transcriptional roles within a single nucleus. Our data support a model in which modulation of the subnuclear concentration of transcription factors acts to organize the nucleus into functionally distinct domains that are essential for the robust regulation of gene expression.

developmental biology↗

Cardiomyocyte alpha-1A adrenergic receptors mitigate post-infarct remodeling and mortality by constraining necroptosis

Activation of alpha-1-adrenergic receptors (1-ARs), particularly the 1A subtype, protects the murine heart against injury, whereas human studies show that 1-AR antagonists (-blockers) may increase the risk of heart failure. We created a cardiomyocyte-specific 1A-AR knockout mouse (cmAKO) to define the mechanisms underlying these effects and to elucidate whether they arise from cardiomyocyte 1A-ARs or systemic factors. Myocardial infarction (MI) resulted in 70% 7-day mortality in cmAKO compared to 10% in wild type (WT) mice. cmAKO mice exhibited exaggerated ventricular remodeling and increased cell death compared to WT mice 3 days post-MI, coupled to upregulation of canonical mediators of necroptosis: receptor-interacting protein (RIP) kinases RIP1 and RIP3 and mixed lineage kinase domain-like protein. An 1A-AR agonist mitigated ischemia-induced cardiomyocyte death and necroptotic signaling in vitro. A RIP1 antagonist abrogated the protective effects of 1A activation in vivo and in vitro. We found that patients at our center who were taking -blockers at the time of MI experienced a higher risk of mortality (hazard ratio 1.53, p=0.029) during 5-year follow-up, providing clinical correlation for our experimental data. Collectively our findings indicate that cardiomyocyte 1A-ARs constrain ischemia-induced necroptosis and suggest caution in the use of -blockers in patients at risk for MI.

pathology↗