Enhancer and Transcription Factor Dynamics during Myeloid Differentiation Reveal an Early Differentiation Block in Cebpa null Progenitors

Cell Reports
Sachin PundhirBo T Porse

Abstract

Transcription factors PU.1 and CEBPA are required for the proper coordination of enhancer activity during granulocytic-monocytic (GM) lineage differentiation to form myeloid cells. However, precisely how these factors control the chronology of enhancer establishment during differentiation is not known. Through integrated analyses of enhancer dynamics, transcription factor binding, and proximal gene expression during successive stages of murine GM-lineage differentiation, we unravel the distinct kinetics by which PU.1 and CEBPA coordinate GM enhancer activity. We find no evidence of a pioneering function of PU.1 during late GM-lineage differentiation. Instead, we delineate a set of enhancers that gain accessibility in a CEBPA-dependent manner, suggesting a pioneering function of CEBPA. Analyses of Cebpa null bone marrow demonstrate that CEBPA controls PU.1 levels and, unexpectedly, that the loss of CEBPA results in an early differentiation block. Taken together, our data provide insights into how PU.1 and CEBPA functionally interact to drive GM-lineage differentiation.

Citations

Mar 20, 2020·Journal of Clinical Medicine·Cristina PanuzzoDaniela Cilloni
Dec 12, 2018·The Journal of Experimental Medicine·Zhiyang ChenK Lenhard Rudolph
Dec 1, 2019·Nature Communications·Theodore P BraunJulia E Maxson
Sep 27, 2020·Proceedings of the National Academy of Sciences of the United States of America·Alexandra MaslovaUNKNOWN Immunological Genome Project
Apr 30, 2021·The Journal of Experimental Medicine·Kelly C HigaJames DeGregori
May 13, 2021·Immunity·Samarth HegdeMiriam Merad
Jul 7, 2021·Cell Death & Disease·Ian Edward GentleGeorg Häcker

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