Abstract
Zbtb1 is a transcription factor that prevents DNA damage and p53-mediated apoptosis in replicating immune progenitors, affecting lymphoid as well as myeloid development when hematopoietic progenitors are in competition in mixed bone marrow chimeras. However, Zbtb1-deficient mice do not have an apparent myeloid deficiency. We report here that Zbtb1-deficient lymphoid-primed multipotent progenitors (LMPPs) are biased to develop towards the myeloid fate in detriment of lymphoid development, contributing to the apparent unaffected myeloid development. Zbtb1 expression was maintained during lymphoid development of LMPP cells but downregulated during myeloid development. Deficiency of Zbtb1 in LMPP cells was sufficient to direct a myeloid fate in lymphoid-inducing conditions and in the absence of myeloid cytokines as shown by upregulation of a myeloid gene signature and the generation of myeloid cells in vitro. Finally, biased myeloid differentiation of Zbtb1-deficient LMPP cells was not due to increased p53-dependent apoptosis as it was not reverted by transgenic Bcl2 expression or p53 deficiency. Altogether, our results show that Zbtb1 expression prevents activation of a default myeloid program in LMPP cells, ensuring the generation of lymphoid cells.
Highlights
Many members of the BTB-ZF (Broad complex, tramtrack, and Bric a brac-zinc finger) family of transcription repressors were shown to play key roles in the development of immune cells [1, 2]
As increased DNA damage and activation of the p53-p21 axis were linked to biased myeloid development of hematopoietic stem cells [11, 12], and as Zbtb1 was shown to prevent DNA damage, we evaluated if Zbtb1deficient immune progenitors presented biased myeloid development
We found a similar expression pattern on Csf1r and Csf2rb, which are markers of myeloid cells and direct myeloid differentiation of HSCs in response to myeloid cytokines [13,14,15,16]. These results show that ScanT lymphoid-primed multipotent progenitors (LMPPs) cells, despite having a similar myeloid potential than wild type cells, differentiate into myeloid cells when cultured in lymphoid inducing conditions, indicating that Zbtb1 is required to repress the myeloid program in LMPP progenitors
Summary
Many members of the BTB-ZF (Broad complex, tramtrack, and Bric a brac-zinc finger) family of transcription repressors were shown to play key roles in the development of immune cells [1, 2]. Zbtb interacts with Kap, allowing the accessibility of Rad to sites of replication stress, which in turn triggers the recruitment of low fidelity DNA polymerases that can bypass the DNA lesion ensuring continuation of DNA synthesis. This process is called translesion DNA synthesis [6]
Sign-in/Register to view highlights & summary 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.
