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

TY - JOUR

T1 - Enhancer and Transcription Factor Dynamics during Myeloid Differentiation Reveal an Early Differentiation Block in Cebpa null Progenitors

AU - Pundhir, Sachin

AU - Bratt Lauridsen, Felicia Kathrine

AU - Schuster, Mikkel Bruhn

AU - Jakobsen, Janus Schou

AU - Ge, Ying

AU - Schoof, Erwin Marten

AU - Rapin, Nicolas Philippe Jean-Pierre

AU - Waage, Johannes

AU - Hasemann, Marie Sigurd

AU - Porse, Bo Torben

N1 - Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2018/5/29

Y1 - 2018/5/29

N2 - 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. Granulocytic-monocytic differentiation is governed by the PU.1 and CEBPA transcription factors (TFs). Here, Pundhir et al. use histone and TF ChIP-seq to demonstrate an unexpected role for CEBPA in controlling PU.1 function. They show that loss of CEBPA results in an early GM lineage differentiation block upstream of CMPs/preGMs.

AB - 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. Granulocytic-monocytic differentiation is governed by the PU.1 and CEBPA transcription factors (TFs). Here, Pundhir et al. use histone and TF ChIP-seq to demonstrate an unexpected role for CEBPA in controlling PU.1 function. They show that loss of CEBPA results in an early GM lineage differentiation block upstream of CMPs/preGMs.

U2 - 10.1016/j.celrep.2018.05.012

DO - 10.1016/j.celrep.2018.05.012

M3 - Journal article

C2 - 29847803

SN - 2211-1247

VL - 23

SP - 2744

EP - 2757

JO - Cell Reports

JF - Cell Reports

IS - 9

ER -