The transcription factors GFI1 and GFI1B as modulators of the innate and acquired immune response

GFI1 and GFI1B are small nuclear proteins of 45 and 37kDa, respectively, that have a simple two-domain structure: The first consists of a group of six c-terminal C₂H₂ zinc finger motifs that are almost identical in sequence and bind to very similar, specific DNA sites. The second is an N-terminal 20 amino acid SNAG domain that can bind to the pocket of the histone demethylase KDM1A (LSD1) near its active site. When bound to DNA, both proteins act as bridging factors that bring LSD1 and associated proteins into the vicinity of methylated substrates, in particular histone H3 or TP53. GFI1 can also bring methyl transferases such as PRMT1 together with its substrates that include the DNA repair proteins MRE11 and 53BP1, thereby enabling their methylation and activation. While GFI1B is expressed almost exclusively in the erythroid and megakaryocytic lineage, GFI1 has clear biological roles in the development and differentiation of lymphoid and myeloid immune cells. GFI1 is required for lymphoid/myeloid and monocyte/granulocyte lineage decision as well as the correct nuclear interpretation of a number of important immune-signaling pathways that are initiated by NOTCH1, interleukins such as IL2, IL4, IL5 or IL7, by the pre TCR or -BCR receptors during early lymphoid differentiation or by T and B cell receptors during activation of lymphoid cells. Myeloid cells also depend on GFI1 at both stages of early differentiation as well as later stages in the process of activation of macrophages through Toll-like receptors in response to pathogen-associated molecular patterns. The knowledge gathered on these factors over the last decades puts GFI1 and GFI1B at the center of many biological processes that are critical for both the innate and acquired immune system.