Orchestration of late events in erythropoiesis by KLF1/EKLF.
OBJECTIVE
Transcriptional regulators provide the molecular and biochemical basis for the cell specific properties and characteristics that follow from their central role in establishing tissue-restricted expression. Precise and sequential control of terminal cell divisions, nuclear condensation, and enucleation are defining characteristics within erythropoietic differentiation. This review is focused on KLF1, a central global regulator of this process.


RESULTS
Studies in the past year have brought a number of proteins that are targets of KLF1 regulation into focus with respect to their roles in terminal erythroid differentiation. Many of these are involved in fine control of the cell cycle at both early (E2F2, Cyclin A2) and later (p18, p27, p19) stages of differentiation, or are directly involved in enucleation (p18, p27). Dramatic biophysical changes controlled at the nuclear lamin by caspase 3 enable histone release and nuclear condensation, whereas dematin association with structural proteins alters the timing of enucleation. Conditional ablation of mDia2 has established its role in late stage cell cycle and enucleation.


CONCLUSIONS
Transcription factors such as KLF1, along with epigenetic modifiers, play crucial roles in establishing the proper onset and progression of terminal differentiation events. Studies from the past year show a remarkable multifaceted convergence on cell cycle control, and establish that the orthochromatic erythroblast stage is a critical nodal point for many of the effects on enucleation. These studies are relevant to understanding the underlying causes of anemia and hematologic disease where defective enucleation predicts a poor clinical outcome.
aDepartment of Cell, Developmental, and Regenerative Biology bBlack Family Stem Cell Institute cTisch Cancer Center dMindich Child Health and Development Institute, Mount Sinai School of Medicine, New York, USA.
Merlin Nithya
MN
Gnanapragasam
James J
JJ
Bieker
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis; D005786:Gene Expression Regulation; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding
D002843:Chromatin; D051741:Kruppel-Like Transcription Factors; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; C080774:erythroid Kruppel-like factor