Mitotic retention of gene expression patterns by the cell fate-determining transcription factor Runx2.
During cell division, cessation of transcription is coupled with mitotic chromosome condensation. A fundamental biological question is how gene expression patterns are retained during mitosis to ensure the phenotype of progeny cells. We suggest that cell fate-determining transcription factors provide an epigenetic mechanism for the retention of gene expression patterns during cell division. Runx proteins are lineage-specific transcription factors that are essential for hematopoietic, neuronal, gastrointestinal, and osteogenic cell fates. Here we show that Runx2 protein is stable during cell division and remains associated with chromosomes during mitosis through sequence-specific DNA binding. Using siRNA-mediated silencing, mitotic cell synchronization, and expression profiling, we identify Runx2-regulated genes that are modulated postmitotically. Novel target genes involved in cell growth and differentiation were validated by chromatin immunoprecipitation. Importantly, we find that during mitosis, when transcription is shut down, Runx2 selectively occupies target gene promoters, and Runx2 deficiency alters mitotic histone modifications. We conclude that Runx proteins have an active role in retaining phenotype during cell division to support lineage-specific control of gene expression in progeny cells.
Young
Daniel W
DW
Department of Cell Biology and Cancer Center, Program in Molecular Medicine, and Information Services, University of Massachusetts Medical School, Worcester, MA 01655-0105, USA.
Hassan
Mohammad Q
MQ
Yang
Xiao-Qing
XQ
Galindo
Mario
M
Javed
Amjad
A
Zaidi
Sayyed K
SK
Furcinitti
Paul
P
Lapointe
David
D
Montecino
Martin
M
Lian
Jane B
JB
Stein
Janet L
JL
van Wijnen
Andre J
AJ
Stein
Gary S
GS
D015153:Blotting, Western; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002877:Chromosomes, Human / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference
D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human