FOG1 requires NuRD to promote hematopoiesis and maintain lineage fidelity within the megakaryocytic-erythroid compartment.
Nuclear factors regulate the development of complex tissues by promoting the formation of one cell lineage over another. The cofactor FOG1 interacts with transcription factors GATA1 and GATA2 to control erythroid and megakaryocyte (MK) differentiation. In contrast, FOG1 antagonizes the ability of GATA factors to promote mast cell (MC) development. Normal FOG1 function in late-stage erythroid cells and MK requires interaction with the chromatin remodeling complex NuRD. Here, we report that mice in which the FOG1/NuRD interaction is disrupted (Fog(ki/ki)) produce MK-erythroid progenitors that give rise to significantly fewer and less mature MK and erythroid colonies in vitro while retaining multilineage capacity, capable of generating MCs and other myeloid lineage cells. Gene expression profiling of Fog(ki/ki) MK-erythroid progenitors revealed inappropriate expression of several MC-specific genes. Strikingly, aberrant MC gene expression persisted in mature Fog(ki/ki) MK and erythroid progeny. Using a GATA1-dependent committed erythroid cell line, select MC genes were found to be occupied by NuRD, suggesting a direct mechanism of repression. Together, these observations suggest that a simple heritable silencing mechanism is insufficient to permanently repress MC genes. Instead, the continuous presence of GATA1, FOG1, and NuRD is required to maintain lineage fidelity throughout MK-erythroid ontogeny.
Gregory
Gregory D
GD
Division of Hematology, Children's Hospital of Philadelphia, PA 19104, USA.
Miccio
Annarita
A
Bersenev
Alexey
A
Wang
Yuhuan
Y
Hong
Wei
W
Zhang
Zhe
Z
Poncz
Mortimer
M
Tong
Wei
W
Blobel
Gerd A
GA
D000818:Animals; D002451:Cell Compartmentation; D002454:Cell Differentiation; D019070:Cell Lineage; D041905:Erythroid Cells / Q000166:cytology* / Q000201:enzymology; D004920:Erythropoiesis; D050982:GATA1 Transcription Factor / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006410:Hematopoiesis; D008407:Mast Cells / Q000378:metabolism; D055015:Megakaryocyte-Erythroid Progenitor Cells / Q000166:cytology / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology* / Q000201:enzymology; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D012097:Repressor Proteins / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C107310:Zfpm1 protein, mouse; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex