Poster Presentation Lorne Infection and Immunity 2023

Characterization of a novel Transcriptional Start Site in human myeloid cells that generates unique NRG1 isoforms (#106)

Miguel MAB Berrocal 1 , Ricardo De Paoli-Iseppi 1 , Marija Dinevska 1 , Sefi Prawer 1 , Samuel Widodo 1 , Nadia Rajab 1 , Matthew Watt 1 , Theo Mantamadiotis 1 , Michael Clark 1 , Christine Wells 1
  1. University of Melbourne, CARLTON, VIC, Australia

Macrophages are homeostatic controllers of most human tissues, controlling cell behavior and tissue architecture through morphogens, cytokines, and growth factors. Macrophages are a primary source of the growth factor Neuregulin-1 (NRG1), which has pleiotropic roles in proliferation and differentiation of the stem cell niche in different tissues, and has been implicated in gut, brain and muscle development and repair. NRG1 presents a variety of isoforms that differ in structure and function; however, it is not yet understood which isoform or combination of isoforms are expressed by macrophages. Here we report a new class of NRG1 that initiates from a unique Transcriptional Start Site (TSS) and appears to be exclusively used by cells of the myeloid lineage, designated NRG1-VII according to the nomenclature conventions of this locus. Long-read sequencing identified up to 9 different transcripts that arise from the use of the novel TSS, some of which show major structural differences from one another due to use of alternative stop codons and 3’UTRs. Expression of NRG1-VII isoforms was confirmed in different myeloid cells, confirming that this is the major TSS in this lineage. There is no evidence that any other cell type outside of this lineage can generate said isoforms. NRG1-VII expression appears to be regulated by monocyte maturation and macrophage differentiation. A subset of macrophages in tissues express NRG1, however the role of these variants in tissue homeostasis or repair is not yet determined