Disease relevance of ZFPM1

• X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction [1].
• Alterations of the FOG-1 face are responsible for dyserythropoietic anemia with thrombocytopenia while R216Q, the only mutation identified in the DNA face, induces X-linked thrombocytopenia with thalassemia (XLTT) [2].
• Absence of mutations in the key megakaryocyte transcriptional regulator FOG-1 in patients with idiopathic myelofibrosis [3].

High impact information on ZFPM1

• These results indicate that FOG-1 is a determinant of GATA factor target gene sensitivity by either facilitating or opposing chromatin occupancy [4].
• Thus, FOG-1 facilitates chromatin occupancy by GATA-1 at sites bound by GATA-2 [5].
• However, at DNase I-hypersensitive site (HS)3 of the beta-globin locus control region, GATA-1-induced histone acetylation was FOG-1-independent [6].
• In contrast, abrogation of GATA1-FOG-1 interaction leads to loss of differentiation, but growth of blocked immature megakaryocytes is controlled [7].
• Previous studies of synthetic and naturally occurring mutant GATA1 molecules demonstrate that DNA-binding and interaction with the essential GATA1 cofactor FOG-1 (via the N-terminal finger) are required for gene expression in terminally differentiating megakaryocytes and for platelet production [7].

Biological context of ZFPM1

• In contrast, GATA-1 bearing a point mutation that impairs FOG-1 binding [GATA-1(V205M)-ER] failed to induce high levels of histone acetylation at this site [6].
• These results indicate that FOG-1 employs distinct mechanisms when cooperating with GATA-1 during transcriptional activation and repression [6].
• Guided by bioinformatic analysis, we demonstrated that selected regions of the Fog1 gene exhibit enhancer activity and in vivo occupancy by GATA-1 [8].
• Mutations in the DNA or FOG-1 binding sites of its N-terminal zinc finger result in different illnesses [2].
• The transcription factor GATA-1, together with its cofactor FOG-1, regulates erythropoiesis and megakaryocytopoiesis [2].

Physical interactions of ZFPM1

• Arg216Gln GATA-1 interacts with FOG-1 similarly with wild-type GATA-1 [1].

Regulatory relationships of ZFPM1

• The mechanisms by which FOG-1 regulates GATA-1 function are unknown [6].

Other interactions of ZFPM1

• Together, these findings suggest that residues of the N finger of GATA-1-facing DNA contribute to GATA-1 function apart from interaction with the cofactor FOG-1 [1].
• GATA-1, FOG-1 and Fli-1 are essential regulators in early- and mid-stages of megakaryocytopoiesis [9].
• GATA-3 inhibitors (such as FOG-1 and ROG) modulate GATA-3 expression by yet unidentified mechanisms [10].

References