Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration.
BMP and Wnt signaling pathways control essential cellular responses through activation of the transcription factors SMAD (BMP) and TCF (Wnt). Here, we show that regeneration of hematopoietic lineages following acute injury depends on the activation of each of these signaling pathways to induce expression of key blood genes. Both SMAD1 and TCF7L2 co-occupy sites with master regulators adjacent to hematopoietic genes. In addition, both SMAD1 and TCF7L2 follow the binding of the predominant lineage regulator during differentiation from multipotent hematopoietic progenitor cells to erythroid cells. Furthermore, induction of the myeloid lineage regulator C/EBPα in erythroid cells shifts binding of SMAD1 to sites newly occupied by C/EBPα, whereas expression of the erythroid regulator GATA1 directs SMAD1 loss on nonerythroid targets. We conclude that the regenerative response mediated by BMP and Wnt signaling pathways is coupled with the lineage master regulators to control the gene programs defining cellular identity.
Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
Eirini
E
Trompouki
Teresa V
TV
Bowman
Lee N
LN
Lawton
Zi Peng
ZP
Fan
Dai-Chen
DC
Wu
Anthony
A
DiBiase
Corey S
CS
Martin
Jennifer N
JN
Cech
Anna K
AK
Sessa
Jocelyn L
JL
Leblanc
Pulin
P
Li
Ellen M
EM
Durand
Christian
C
Mosimann
Garrett C
GC
Heffner
George Q
GQ
Daley
Robert F
RF
Paulson
Richard A
RA
Young
Leonard I
LI
Zon
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006410:Hematopoiesis; D006801:Humans; D012038:Regeneration; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism; D060449:Wnt Signaling Pathway; D015027:Zebrafish
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D051898:Smad1 Protein; D058118:Transcription Factor 7-Like 2 Protein