Knocking down Israa, the Zmiz1 intron-nested gene, unveils interrelated T cell activation functions in mouse

• Main Authors: Noureddine Ben Khalaf, Wedad Al-Mashoor, Azhar Saeed, Wassim Raslan, Halla Bakheit, Ameera Abdulhadi, Ammar Marouani, Safa Taha, Moiz Bakhiet, M. Dahmani Fathallah
• Format: Article
• Language: English
• Published: Elsevier 2021-09-01
• Series: Biochemistry and Biophysics Reports
• Subjects: T cell activation; Nested gene; Knock-out; Fyn; Elf-1
• Online Access: http://www.sciencedirect.com/science/article/pii/S2405580821001953

We previously reported Israa (immune-system-released activating agent), a novel gene nested in intron 6 of the mouse Zmiz1 gene. Zmiz1 is involved in several functions such as fertility and T cell development and its knockout leads to non-viable embryos. We also reported ISRAA's expression in lymphoid organs, particularly in the thymus CD3+ T cells during all developmental stages. In addition, we showed that ISRAA is a binding partner of Fyn and Elf-1 and regulates the expression of T cell activation-related genes in vitro. In this paper, we report the generation and characterization of an Israa−/− constitutive knockout mouse. The histological study shows that Israa−/− mice exhibit thymus and spleen hyperplasia. Israa−/− derived T cells showed increased proliferation compared to the wild-type mice T cells. Moreover, gene expression analysis revealed a set of differentially expressed genes in the knockout and wild-type animals during thymus development (mostly genes of T cell activation pathways). Immunological phenotyping of the thymocytes and splenocytes of Israa−/- showed no difference with those of the wild-type. Moreover, we observed that knocking out the Zmiz1 intron embedded Israa gene does not affect mice fertility, thus does not disturb this Zmiz1 function. The characterization of the Israa−/- mouse confirms the role ISRAA plays in the expression regulation of genes involved in T cell activation established in vitro. Taken together, our findings point toward a potential functional interrelation between the intron nested Israa gene and the Zmiz1 host gene in regulating T cell activation. This constitutively Israa−/− mice can be a good model to study T cell activation and to investigate the relationship between host and intron-nested genes.