Proteomics

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Pathogenesis of dominant-negative mutant GFI1B and associated proteomic abnormalities in megakaryocytes and platelets


ABSTRACT: Dominant-negative mutations in transcription factor Growth Factor Independence-1B (GFI1B) cause a bleeding disorder characterized by a plethora of megakaryocyte and platelet abnormalities. The deregulated molecular mechanisms and pathways are unknown. Here we show that normal and mutant GFI1B interacted most strongly with the LSD1-RCOR-HDAC corepressor complex in megakaryoblasts. Sequestration of this complex by mutant GFI1B and chemical separation of GFI1B from LSD1 induced abnormalities in normal megakaryocytes comparable to those seen in patients. Megakaryocytes derived from GFI1B-mutant induced pluripotent stem cells (iPSC) also phenocopied abnormalities seen in patients. Proteome studies on normal and mutant iPSC-derived megakaryocytes identified a multitude of deregulated pathways downstream of mutant GFI1B. Proteome studies on primary normal and GFI1B-mutant platelets showed reduced expression of proteins implicated in platelet function, and sustained expression of proteins normally downregulated during megakaryocyte differentiation. Thus, GFI1B regulates a broad developmental program during megakaryopoiesis. Mutant GFI1B deregulates this program through LSD1-RCOR-HDAC sequestering.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Platelet, Platelet, Primary Cell, Megakaryocyte

SUBMITTER: Johanna Koornneef  

LAB HEAD: Alexander Meijer

PROVIDER: PXD009020 | Pride | 2019-01-25

REPOSITORIES: Pride

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Publications


Dominant-negative mutations in the transcription factor Growth Factor Independence-1B (GFI1B), such as GFI1B<sup>Q287*</sup>, cause a bleeding disorder characterized by a plethora of megakaryocyte and platelet abnormalities. The deregulated molecular mechanisms and pathways are unknown. Here we show that both normal and Q287* mutant GFI1B interacted most strongly with the lysine specific demethylase-1 - REST corepressor - histone deacetylase (LSD1-RCOR-HDAC) complex in megakaryoblasts. Sequestra  ...[more]

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