student profile: Mr Taylor Syme


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Thesis work

Thesis title: Strawberry notch homolog 2 is a repressor of a subset of IL-6 responsive genes in the murine CNS

Supervisors: Iain CAMPBELL , Hannah NICHOLAS

Thesis abstract:

Strawberry notch homolog 2 (Sbno2) is a putative transcription factor which is constitutively expressed in the central nervous system and is strongly upregulated by various cytokines such as IL-6. Little is known concerning its role in the healthy or inflamed CNS, therefore we generated a mouse model for the deletion of Sbno2 (Sbno2-GKO) to further delineate its function. In primary cultures of wild-type astrocytes, SBNO2 protein production peaked at 6h post-IL6 treatment. This time point was chosen to perform a microarray analysis which revealed an over-representation of genes in Sbno2-GKO astrocytes associated with the innate host response, particularly from the Guanylate-Binding Protein and Immunity-Related GTPases families. Validation of select genes showed that Nlrc5, H2-K1, Rnf19b, Icam1, Bmpr1b had higher overall expression than in WT cells. In response to IL-6 treatment, Irgm1, Igtp, Tgtp, Gbp2, Rnf19b, Icam1, Bmpr1b, Irf1, and Fos exhibited a dysregulated response with heightened and delayed peak expression levels. Conversely, in transduced NIH3T3 fibroblasts overproducing Sbno2, Nlrc5 and H2-K1 were lower overall and a dampened response to IL-6 was seen for Gbp2, Socs3, Serpina3n, Stat2, Irf1, and Rnf19b. While Irgm1, Igtp, Tgtp, and Ifi47 also exhibited dampened responses at 2h, they remained elevated above control cell levels at 6h and 12h. These findings were recapitulated in vivo in a cross between Sbno2-GKO and the GFAP-IL6 mouse model which has chronic astroglial IL-6 production at pathophysiological levels. Expression of Nlrc5, H2-K1, Irgm1, Igtp, Gbp2, Icam1, Irf1, as well as Timp1 and Serpina3n was significantly increased in the Sbno2-GKOxGFAP-IL6 brain compared with GFAP-IL6. The findings reveal Sbno2 to be a transcriptional repressor in the murine CNS. In particular, Sbno2 may contribute to a novel regulatory mechanism in the cellular response to IL-6 which underpins the ability of this cytokine to mediate inflammation in the CNS.

Selected publications

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Journals

  • Grill, M., Syme, T., Nocon, A., Lu, A., Hancock, D., Rose-John, S., Campbell, I. (2015). Strawberry notch homolog 2 is a novel inflammatory response factor predominantly but not exclusively expressed by astrocytes in the central nervous system. GLIA, 63(10), 1738-1752. [More Information]

2015

  • Grill, M., Syme, T., Nocon, A., Lu, A., Hancock, D., Rose-John, S., Campbell, I. (2015). Strawberry notch homolog 2 is a novel inflammatory response factor predominantly but not exclusively expressed by astrocytes in the central nervous system. GLIA, 63(10), 1738-1752. [More Information]

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