CTCF depletion alters chromatin structure and transcription of myeloid-specific factors.
Differentiation is a multistep process tightly regulated and controlled by complex transcription factor networks. Here, we show that the rate of differentiation of common myeloid precursor cells increases after depletion of CTCF, a protein emerging as a potential key factor regulating higher-order chromatin structure. We identified CTCF binding in the vicinity of important transcription factors regulating myeloid differentiation and showed that CTCF depletion impacts on the expression of these genes in concordance with the observed acceleration of the myeloid commitment. Furthermore, we observed a loss of the histone variant H2A.Z within the selected promoter regions and an increase in non-coding RNA transcription upstream of these genes. Both abnormalities suggest a global chromatin structure destabilization and an associated increase of non-productive transcription in response to CTCF depletion but do not drive the CTCF-mediated transcription alterations of the neighbouring genes. Finally, we detected a transient eviction of CTCF at the Egr1 locus in correlation with Egr1 peak of expression in response to lipopolysaccharide (LPS) treatment in macrophages. This eviction is also correlated with the expression of an antisense non-coding RNA transcribing through the CTCF-binding region indicating that non-coding RNA transcription could be the cause and the consequence of CTCF eviction.
Section of Experimental Haematology, Leeds Institute of Cancer Studies and Pathology, University of Leeds, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK.
Lylia
L
Ouboussad
Sarah
S
Kreuz
Pascal F
PF
Lefevre
D000818:Animals; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002843:Chromatin / Q000737:chemistry*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D021901:DNA, Intergenic / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056426:Genetic Loci / Q000235:genetics; D006657:Histones / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D012097:Repressor Proteins / Q000172:deficiency* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000097722:Cohesins
D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D021901:DNA, Intergenic; D051766:Early Growth Response Protein 1; D006657:Histones; D008070:Lipopolysaccharides; D012097:Repressor Proteins; D014157:Transcription Factors; D000097722:Cohesins; C000619698:Ctcf protein, mouse; C486109:Egr1 protein, mouse
CTCF; H2A.Z; RNA polymerase II; myeloid; non-coding RNA; transcription