E2F1 coregulates cell cycle genes and chromatin components during the transition of oligodendrocyte progenitors from proliferation to differentiation.
Cell cycle exit is an obligatory step for the differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating cells. A key regulator of the transition from proliferation to quiescence is the E2F/Rb pathway, whose activity is highly regulated in physiological conditions and deregulated in tumors. In this paper we report a lineage-specific decline of nuclear E2F1 during differentiation of rodent OPC into oligodendrocytes (OLs) in developing white matter tracts and in cultured cells. Using chromatin immunoprecipitation (ChIP) and deep-sequencing in mouse and rat OPCs, we identified cell cycle genes (i.e., Cdc2) and chromatin components (i.e., Hmgn1, Hmgn2), including those modulating DNA methylation (i.e., Uhrf1), as E2F1 targets. Binding of E2F1 to chromatin on the gene targets was validated and their expression assessed in developing white matter tracts and cultured OPCs. Increased expression of E2F1 gene targets was also detected in mouse gliomas (that were induced by retroviral transformation of OPCs) compared with normal brain. Together, these data identify E2F1 as a key transcription factor modulating the expression of chromatin components in OPC during the transition from proliferation to differentiation.
Departments of Neuroscience, Genetics and Genomics, and Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Center for Neuroscience Research, Children's National Medical Center, George Washington University, Washington, DC 20010-2970, and Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10032.
Laura
L
Magri
Victoria A
VA
Swiss
Beata
B
Jablonska
Liang
L
Lei
Xiomara
X
Pedre
Martin
M
Walsh
Weijia
W
Zhang
Vittorio
V
Gallo
Peter
P
Canoll
Patrizia
P
Casaccia
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005260:Female; D018816:Genes, cdc / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D055495:Neurogenesis / Q000502:physiology*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
D002843:Chromatin; D050687:E2F1 Transcription Factor
brain; cell cycle; chromatin; development; tumor