PMID- 33692344
OWN - NLM
STAT- MEDLINE
DCOM- 20210409
LR  - 20210409
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 12
IP  - 1
DP  - 2021 Mar 10
TI  - The epigenetic pioneer EGR2 initiates DNA demethylation in differentiating 
      monocytes at both stable and transient binding sites.
PG  - 1556
LID - 10.1038/s41467-021-21661-y [doi]
LID - 1556
AB  - The differentiation of human blood monocytes (MO), the post-mitotic precursors of 
      macrophages (MAC) and dendritic cells (moDC), is accompanied by the active 
      turnover of DNA methylation, but the extent, consequences and mechanisms of DNA 
      methylation changes remain unclear. Here, we profile and compare epigenetic 
      landscapes during IL-4/GM-CSF-driven MO differentiation across the genome and 
      detect several thousand regions that are actively demethylated during culture, 
      both with or without accompanying changes in chromatin accessibility or 
      transcription factor (TF) binding. We further identify TF that are globally 
      associated with DNA demethylation processes. While interferon regulatory factor 4 
      (IRF4) is found to control hallmark dendritic cell functions with less impact on 
      DNA methylation, early growth response 2 (EGR2) proves essential for MO 
      differentiation as well as DNA methylation turnover at its binding sites. We also 
      show that ERG2 interacts with the 5mC hydroxylase TET2, and its consensus binding 
      sequences show a characteristic DNA methylation footprint at demethylated sites 
      with or without detectable protein binding. Our findings reveal an essential role 
      for EGR2 as epigenetic pioneer in human MO and suggest that active DNA 
      demethylation can be initiated by the TET2-recruiting TF both at stable and 
      transient binding sites.
FAU - Mendes, Karina
AU  - Mendes K
AD  - Department of Internal Medicine III, University Hospital Regensburg, 93053, 
      Regensburg, Germany.
AD  - Universidade Catolica Portuguesa, Center for Interdisciplinary Research in Health 
      (CIIS), Institute of Health Sciences (ICS), Viseu, Portugal.
FAU - Schmidhofer, Sandra
AU  - Schmidhofer S
AD  - Department of Internal Medicine III, University Hospital Regensburg, 93053, 
      Regensburg, Germany.
AD  - AstraZeneca, 22880, Wedel, Deutschland.
FAU - Minderjahn, Julia
AU  - Minderjahn J
AD  - Department of Internal Medicine III, University Hospital Regensburg, 93053, 
      Regensburg, Germany.
AD  - Sandoz GmbH, 6336, Langkampfen, Austria.
FAU - Glatz, Dagmar
AU  - Glatz D
AD  - Department of Internal Medicine III, University Hospital Regensburg, 93053, 
      Regensburg, Germany.
AD  - Chromatin Structure and Cellular Senescence Research Unit, Maisonneuve-Rosemont 
      Hospital Research Centre, Montreal, QC, H1T 2M4, Canada.
FAU - Kiesewetter, Claudia
AU  - Kiesewetter C
AD  - Department of Internal Medicine III, University Hospital Regensburg, 93053, 
      Regensburg, Germany.
AD  - Labor Kneissler, 93133, Burglengenfeld, Germany.
FAU - Raithel, Johanna
AU  - Raithel J
AD  - Regensburg Centre for Interventional Immunology, University Hospital Regensburg, 
      93053, Regensburg, Germany.
FAU - Wimmer, Julia
AU  - Wimmer J
AD  - Department of Internal Medicine III, University Hospital Regensburg, 93053, 
      Regensburg, Germany.
AD  - Deutsches Patent- und Markenamt, 80331, Munchen, Germany.
FAU - Gebhard, Claudia
AU  - Gebhard C
AD  - Regensburg Centre for Interventional Immunology, University Hospital Regensburg, 
      93053, Regensburg, Germany.
FAU - Rehli, Michael
AU  - Rehli M
AUID- ORCID: 0000-0003-3992-932X
AD  - Department of Internal Medicine III, University Hospital Regensburg, 93053, 
      Regensburg, Germany. michael.rehli@ukr.de.
AD  - Regensburg Centre for Interventional Immunology, University Hospital Regensburg, 
      93053, Regensburg, Germany. michael.rehli@ukr.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210310
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (EGR2 protein, human)
RN  - 0 (Early Growth Response Protein 2)
SB  - IM
MH  - Binding Sites
MH  - Cells, Cultured
MH  - Chromatin Immunoprecipitation Sequencing
MH  - DNA Demethylation
MH  - DNA Methylation/genetics/physiology
MH  - Early Growth Response Protein 2/chemistry/genetics/*metabolism
MH  - Humans
MH  - Immunoblotting
MH  - Immunoprecipitation
MH  - Mass Spectrometry
MH  - Monocytes/*metabolism
MH  - Protein Binding
MH  - RNA-Seq
PMC - PMC7946903
COIS- The authors declare no competing interests.
EDAT- 2021/03/12 06:00
MHDA- 2021/04/10 06:00
PMCR- 2021/03/10
CRDT- 2021/03/11 06:09
PHST- 2020/07/09 00:00 [received]
PHST- 2021/02/04 00:00 [accepted]
PHST- 2021/03/11 06:09 [entrez]
PHST- 2021/03/12 06:00 [pubmed]
PHST- 2021/04/10 06:00 [medline]
PHST- 2021/03/10 00:00 [pmc-release]
AID - 10.1038/s41467-021-21661-y [pii]
AID - 21661 [pii]
AID - 10.1038/s41467-021-21661-y [doi]
PST - epublish
SO  - Nat Commun. 2021 Mar 10;12(1):1556. doi: 10.1038/s41467-021-21661-y.