MicroRNA modulates expression of atrial natiuretic peptide

Natural genetic variants in the 3’ untranslated region of NPPA, the gene that encodes the vasodilator atrial natriuretic peptide (ANP), have previously been linked to blood pressure. Pankaj Arora and colleagues found that individuals with the AG genotype had up to 50% higher levels of ANP when fed a high salt diet compared to individuals with the AA genotype. Additionally, they identified a microRNA, miR-425, that is expressed in human atria and ventricles. Arora and colleagues demonstrated that miR-425 silenced NPPA mRNA encoded by the A allele, but not the G allele. These findings indicate that therapeutics targeting miR-425 could potentially be used to increase ANP levels to treat salt-induced hypertension.

β-globin gene transfer in human bone marrow for sickle cell disease

In this episode of JCI's Author's Take, Donald Kohn of UCLA describes his group's efforts to develop a method to safely and effectively modify patient bone marrow to treat sickle cell disease. Sickle cell disease (SCD) is an autosomal recessive disorder caused by mutations in hemoglobin (HBB) that leads to rigid, deformed red blood cells, as seen in the accompanying image. A small number of patients have been successfully treated with allogeneic hematopoietic stem cell (HSC) transplantation; however, there are several drawbacks and complications associated with this procedure. Many complications could potentially be avoided by performing an autologous HSC transplant in combination with gene therapy to over-ride the defective hemoglobin gene. Zulema Romero, Donald Kohn, and colleagues investigated the utility of a lentiviral vector encoding a human b-globin gene engineered to impede sickle hemoglobin polymerization. The vector efficiently transduced bone marrow cells from SCD patients and expressed the engineered globin gene to prevent sickling of red blood cells and the transduced cells were successfully transplanted into immunocompromised mice, indicating that this method could potentially be used to treat SCD.

Transcription factor ATF3 links host adaptive response to breast cancer metastasis

Tsonwin Hai and colleagues discuss how the transcription factor ATF3 acts as a key regulator of the host immune response and as a contributor to co-option of the host by cancer cells to promote metastasis. Highlights:

• ATF3 is expressed in immune mononuclear cells in human breast tumors and is associated with worse clinical outcomes.
• Host ATF3 expression facilitates breast cancer metastasis.
• ATF3 alters the host systemic environment, increasing the number of tumor-associated macrophages.
• Cancer-induced ATF3 expression in mononuclear cells alters gene expression and bioactivity to contribute to host-enhanced metastasis.

Reducing TMPRSS6 ameliorates hemochromatosis and beta-thalassemia in mice

Brett Monia and Stefano Rivella discuss how reduction of TMPRSS6 expression with antisense oligonucleotides ameliorates iron metabolism disorders in mice. Highlights:

• Iron metabolism is a complex and heavily regulated process that is required for basic physiological functions, including hematopoiesis and host immune responses.
• Hemochromatosis and β-thalassemia are iron overload disorders caused by low levels of hepcidin, the hormone that regulates iron absorption.
• Antisense oligonucleotides (ASOs) lowered Tmprss6 RNA and elevated hepcidin levels.
• TMPRSS6 ASO treatment reversed anemia and iron overload in a mouse model of β-thalassemia.

The TGR5 receptor mediates bile acid-induced itch and analgesia

The liver secretes bile acids to aid in the digestion of fats. Cholestasis is a condition in which the bile flow from the liver to the duodenum is impeded. Patients with the disease exhibit itchiness (pruritis) and cannot sense pain (analgesia). The molecular mechanisms mediating these effects are unknown. Carlos Corvera of UCSF and Nigel Bunnett of Monash University discuss their study demonstrating that bile acids cause itch and analgesia by activating the TGR5 receptor in neurons. Highlights:

• TGR5 is expressed in neurons in mouse dorsal root ganglia and spinal cord, which transmit itch and pain signals.
• Stimulation of TGR5 induced the release of itch and analgesia transmitting molecules, including gastrin-releasing peptide and leucine-enkephalin.
• Intradermal injection of bile acids stimulated scratching behavior that was TGR5-dependent.
• Bile acids activate TGR5 on sensory nerves to transmit itch and analgesia, suggesting that these mechanisms contribute to pruritus and analgesia during cholestatic liver diseases.