TY - JOUR
T1 - Divergent functions of hematopoietic transcription factors in lineage priming and differentiation during erythro-megakaryopoiesis
AU - Pimkin, Maxim
AU - Kossenkov, Andrew V.
AU - Mishra, Tejaswini
AU - Morrissey, Christapher S.
AU - Wu, Weisheng
AU - Keller, Cheryl A.
AU - Blobel, Gerd A.
AU - Lee, Dongwon
AU - Beer, Michael A.
AU - Hardison, Ross C.
AU - Weiss, Mitchell J.
N1 - Publisher Copyright:
© 2014 Pimkin et al.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, TAL1, and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary cultured megakaryocytes (MEG) and primary erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genomewide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-associated cis-regulatory modules (CRMs) in multipotential progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential progenitor via overlapping and divergent functions of shared hematopoietic transcription factors.
AB - Combinatorial actions of relatively few transcription factors control hematopoietic differentiation. To investigate this process in erythro-megakaryopoiesis, we correlated the genome-wide chromatin occupancy signatures of four master hematopoietic transcription factors (GATA1, GATA2, TAL1, and FLI1) and three diagnostic histone modification marks with the gene expression changes that occur during development of primary cultured megakaryocytes (MEG) and primary erythroblasts (ERY) from murine fetal liver hematopoietic stem/progenitor cells. We identified a robust, genomewide mechanism of MEG-specific lineage priming by a previously described stem/progenitor cell-expressed transcription factor heptad (GATA2, LYL1, TAL1, FLI1, ERG, RUNX1, LMO2) binding to MEG-associated cis-regulatory modules (CRMs) in multipotential progenitors. This is followed by genome-wide GATA factor switching that mediates further induction of MEG-specific genes following lineage commitment. Interaction between GATA and ETS factors appears to be a key determinant of these processes. In contrast, ERY-specific lineage priming is biased toward GATA2-independent mechanisms. In addition to its role in MEG lineage priming, GATA2 plays an extensive role in late megakaryopoiesis as a transcriptional repressor at loci defined by a specific DNA signature. Our findings reveal important new insights into how ERY and MEG lineages arise from a common bipotential progenitor via overlapping and divergent functions of shared hematopoietic transcription factors.
UR - http://www.scopus.com/inward/record.url?scp=84897559899&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84897559899&partnerID=8YFLogxK
U2 - 10.1101/gr.164178.113
DO - 10.1101/gr.164178.113
M3 - Article
C2 - 25319996
AN - SCOPUS:84897559899
SN - 1088-9051
VL - 24
SP - 1932
EP - 1944
JO - Genome research
JF - Genome research
IS - 12
ER -