Background: Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. La ribonucleoprotein domain family member 7 (LARP7) is a master regulator that governs the DNA damage response and RNAPII pausing pathway, but the role of it in heart failure pathogenesis is incompletely understood. Methods: We assessed LARP7 expression in human HF, and in non-human primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific LARP7 knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated LARP7 somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 (AAV9) and ataxia telangiectasia mutated protein (ATM) inhibitor. The therapeutic potential of LARP7-regulated pathways in heart failure was tested in a mouse myocardial infarction model. Results: LARP7 was profoundly downregulated in failing human hearts and in non-human primate and murine hearts after myocardial infarction (MI). Low LARP7 levels in failing hearts was linked to elevated reactive oxygen species (ROS), which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive LARP7 knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 stability and deacetylase activity which impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after MI by either AAV-mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart. Conclusions: LARP7 is essential for mitochondrial biogenesis, energy production and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts due to activation of the ATM pathway contributes to heart failure pathogenesis, and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in heart failure.

Cell behaviors are dictated by epigenetic and transcriptional programs. Little is known about how extracellular stimuli modulate these programs to reshape gene expression and control cell behavioral responses. Here, we interrogated the epigenetic and transcriptional response of endothelial cells to VEGFA treatment and found rapid chromatin changes that mediate broad transcriptomic alterations. VEGFA-responsive genes were associated with active promoters, but changes in promoter histone marks were not tightly linked to gene expression changes. VEGFA altered transcription factor occupancy and the distal epigenetic landscape, which profoundly contributed to VEGFA-dependent changes in gene expression. Integration of gene expression, dynamic enhancer, and transcription factor occupancy changes induced by VEGFA yielded a VEGFA-regulated transcriptional regulatory network, which revealed that the small MAF transcription factors are master regulators of the VEGFA transcriptional program and angiogenesis. Collectively these results revealed that extracellular stimuli rapidly reconfigure the chromatin landscape to coordinately regulate biological responses.

Attenuated DNA repair leads to genomic instability and tumorigenesis. BRCA1/BARD1 are the best-known tumor suppressors that promote homology recombination (HR) and arrest cell cycle. However, it remains ambiguous whether and how their E3 ligase activity regulates HR. Here, we demonstrate that upon genotoxic stress, BRCA1 together with BARD1 catalyzes the K48 polyubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degrades it through the 26S ubiquitin-proteasome pathway. Depleting LARP7 suppresses the expression of CDK1 complex, arrests the cell at the G2/M DNA damage checkpoint, and reduces BRCA2 phosphorylation, which thereby facilitates RAD51 recruitment to damaged DNA to enhance HR. Importantly, LARP7 depletion observed in breast cancer patients leads to chemoradiotherapy resistance both in vitro and in vivo. Altogether, this study unveils a mechanism by which BRCA1/BARD1 control HR and cell cycle, and highlights LARP7 as a potential target for cancer prevention and therapy.