Abstract
A regulatory circuit that controls myeloid versus B lymphoid cell fate in hematopoietic progenitors has been proposed, in which a network of the transcription factors Egr1/2, Nab, Gfi1 and PU.1 forms the core element. Here we show that a direct link between Gfi1, the transcription factor E2A and its inhibitor Id1 is a critical element of this regulatory circuit. Our data suggest that a certain threshold of Gfi1 is required to gauge E2A activity by adjusting levels of Id1 in multipotent progenitors, which are the first bipotential myeloid/lymphoid-restricted progeny of hematopoietic stem cells. If Gfi1 levels are high, Id1 is repressed enabling E2A to activate a specific set of B lineage genes by binding to regulatory elements for example the IL7 receptor gene. If Gfi1 levels fall below a threshold, Id1 expression increases and renders E2A unable to function, which prevents hematopoietic progenitors from engaging along the B lymphoid lineage.
Highlights
B-lymphocytes are the principal antibody producing cells and are indispensable for an efficient humoral immune response
During the analysis of these mice, we noticed that when the Neo cassette was not deleted, the expression level of human Gfi1 was reduced to about 20–30% of the expression level of the control WT or KI mice without Neo cassette (Fig 1A and 1B) [35]. This provided us with several mouse models expressing different Gfi1 levels (Fig 1A and 1B): WT mice expressing a normal level of murine Gfi1, KI mice expressing a normal level of human Gfi1 instead of the murine Gfi1, heterozygote mice for Gfi1 (Het) expressing around 50–60% of WT Gfi1 levels, animals expressing a reduced level of human Gfi1 and KO mice that were previously described [31] and completely lack Gfi1 expression (Fig 1A and 1B)
We demonstrate that Gfi1 mediates this function by enabling the transcription factor E2A to activate a specific set of target genes that are critical for early B cell development
Summary
B-lymphocytes are the principal antibody producing cells and are indispensable for an efficient humoral immune response. A subset of MPP cells that express Flt receptor, called lymphoid primed multipotent progenitors (LMPPs) [3, 4] become committed to the lymphoid lineage and generate the common lymphoid progenitors, CLPs [3, 5, 6]. Under specific conditions, both CLPs and LMPPs can generate T and B cells [7,8,9]. They continue to differentiate along multiple stages until functional effector B cells [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
