title: Global transcriptome and chromatin occupancy analysis reveal the short isoform of GATA1 is deficient for erythroid specification and gene expression.
abstract: GATA1 is a master transcriptional regulator of the differentiation of several related myeloid blood cell types, including erythrocytes and megakaryocytes. Germ-line mutations that cause loss of full length GATA1, but allow for expression of the short isoform (GATA1s), are associated with defective erythropoiesis in a subset of patients with Diamond Blackfan Anemia. Despite extensive studies of GATA1s in megakaryopoiesis, the mechanism by which GATA1s fails to support normal erythropoiesis is not understood. In this study, we used global gene expression and chromatin occupancy analysis to compare the transcriptional activity of GATA1s to GATA1. We discovered that compared to GATA1, GATA1s is less able to activate the erythroid gene expression program and terminal differentiation in cells with dual erythroid-megakaryocytic differentiation potential. Moreover, we found that GATA1s bound to many of its erythroid-specific target genes less efficiently than full length GATA1. These results suggest that the impaired ability of GATA1s to promote erythropoiesis in DBA may be caused by failure to occupy erythroid-specific gene regulatory elements.
authors: Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA Present address Cincinnati Children's Hospital, Cincinnati, OH, USA.
authors: Timothy M
authors: TM
authors: Chlon
authors: Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA.
authors: Maureen
authors: M
authors: McNulty
authors: Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA.
authors: Benjamin
authors: B
authors: Goldenson
authors: Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA.
authors: Alexander
authors: A
authors: Rosinski
authors: Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA j-crispino@northwestern.edu.
authors: John D
authors: JD
authors: Crispino
mesh_terms: D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism*; D004920:Erythropoiesis / Q000235:genetics; D050982:GATA1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D059372:Nucleotide Motifs; D011485:Protein Binding; D059368:RNA Isoforms; D034061:Thrombopoiesis / Q000235:genetics; D059467:Transcriptome
chemical_list: D050982:GATA1 Transcription Factor; D059368:RNA Isoforms