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. 2022 Mar;70(3):572-589.
doi: 10.1002/glia.24124. Epub 2021 Dec 4.

Context-dependent transcriptional regulation of microglial proliferation

Sarah Belhocine  1   2 , André Machado Xavier  1   2 , Félix Distéfano-Gagné  1   2 , Stéphanie Fiola  1 , Serge Rivest  1   2 , David Gosselin  1   2
Affiliations

Context-dependent transcriptional regulation of microglial proliferation

Sarah Belhocine et al. Glia. 2022 Mar.

Abstract

Microglia proliferate during brain development and brain lesions, but how this is coordinated at the transcriptional level is not well understood. Here, we investigated fundamental aspects of the transcriptional process associated with proliferation of mouse microglia during postnatal development and in adults in a model of induced microglial depletion-repopulation. While each proliferative subset displayed globally a distinct signature of gene expression, they also co-expressed a subgroup of 1370 genes at higher levels than quiescent microglia. Expression of these may be coordinated by one of two mechanisms of regulation with distinct properties. A first mechanism augments expression of genes already expressed in quiescent microglia and is subject to regulation by Klf/Sp, Nfy, and Ets transcription factors. Alternatively, a second mechanism enables de novo transcription of cell cycle genes and requires additional regulatory input from Lin54 and E2f transcription factors. Of note, transcriptional upregulation of E2f1 and E2f2 family members may represent a critical regulatory checkpoint to enable microglia to achieve efficient cell cycling. Furthermore, analysis of the activity profile of the repertoire of promoter-distal genomic regulatory elements suggests a relatively restricted role for these elements in coordinating cell cycle gene expression in microglia. Overall, proliferating microglia integrates regulation of cell cycle gene expression with their broader, context-dependent, transcriptional landscape.

Keywords: brain development; cell cycle; epigenomics; genomic regulatory elements; microglia; mouse; transcription.

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References

REFERENCES

    1. Askew, K., Li, K., Olmos-Alonso, A., Garcia-Moreno, F., Liang, Y., Richardson, P., Tipton, T., Chapman, M. A., Riecken, K., Beccari, S., Sierra, A., Molnar, Z., Cragg, M., Garaschuk, O., Perry, V. H., & Gomez-Nicola, D. (2017). Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Reports, 18(2), 391-405. https://doi.org/10.1016/j.celrep.2016.12.041
    1. Aziz, A., Soucie, E., Sarrazin, S., & Sieweke, M. H. (2009). MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages. Science, 326(5954), 867-871. https://doi.org/10.1126/science.1176056
    1. Basak, O., van de Born, M., Korving, J., Beumer, J., van der Elst, S., van Es, J. H., & Clevers, H. (2014). Mapping early fate determination in Lgr5+ crypt stem cells using a novel Ki67-RFP allele. The EMBO Journal, 33(18), 2057-2068. https://doi.org/10.15252/embj.201488017
    1. Benatti, P., Dolfini, D., Vigano, A., Ravo, M., Weisz, A., & Imbriano, C. (2011). Specific inhibition of NF-Y subunits triggers different cell proliferation defects. Nucleic Acids Research, 39(13), 5356-5368. https://doi.org/10.1093/nar/gkr128
    1. Bernstein, B. E., Mikkelsen, T. S., Xie, X., Kamal, M., Huebert, D. J., Cuff, J., Fry, B., Meissner, A., Werning, M., Plath, K., Jaenisch, R., Wagschal, A., Feil, R., Schreiber, S. L., & Lander, E. S. (2006). A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell, 125(2), 315-326. https://doi.org/10.1016/j.cell.2006.02.041

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