Epigenetic silencing of the c-fms locus during B-lymphopoiesis occurs in discrete steps and is reversible.
The murine c-fms (Csf1r) gene encodes the macrophage colony-stimulating factor receptor, which is essential for macrophage development. It is expressed at a low level in haematopoietic stem cells and is switched off in all non-macrophage cell types. To examine the role of chromatin structure in this process we studied epigenetic silencing of c-fms during B-lymphopoiesis. c-fms chromatin in stem cells and multipotent progenitors is in the active conformation and bound by transcription factors. A similar result was obtained with specified common myeloid and lymphoid progenitor cells. In developing B cells, c-fms chromatin is silenced in distinct steps, whereby first the binding of transcription factors and RNA expression is lost, followed by a loss of nuclease accessibility. Interestingly, regions of de novo DNA methylation in B cells overlap with an intronic antisense transcription unit that is differently regulated during lymphopoiesis. However, even at mature B cell stages, c-fms chromatin is still in a poised conformation and c-fms expression can be re-activated by conditional deletion of the transcription factor Pax5.
Molecular Medicine Unit, St James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
Hiromi
H
Tagoh
Alexandra
A
Schebesta
Pascal
P
Lefevre
Nicola
N
Wilson
David
D
Hume
Meinrad
M
Busslinger
Constanze
C
Bonifer
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D020868:Gene Silencing; D016236:Genes, fms; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D038041:Lymphopoiesis / Q000502:physiology*; D051379:Mice; D009690:Nucleic Acid Conformation; D039904:Pluripotent Stem Cells / Q000502:physiology; D011401:Promoter Regions, Genetic; D016372:RNA, Antisense / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism
D002843:Chromatin; D006657:Histones; D016372:RNA, Antisense; D014157:Transcription Factors