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

Sachin Pundhir, Felicia Kathrine Bratt Lauridsen, Mikkel Bruhn Schuster, Janus Schou Jakobsen, Ying Ge, Erwin Marten Schoof, Nicolas Rapin, Johannes Waage, Marie Sigurd Hasemann, Bo Torben Porse

    40 Citationer (Scopus)

    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.

    OriginalsprogEngelsk
    TidsskriftCell Reports
    Vol/bind23
    Udgave nummer9
    Sider (fra-til)2744-2757
    Antal sider14
    DOI
    StatusUdgivet - 29 maj 2018

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