title: Regulation of erythroid differentiation by miR-376a and its targets.
abstract: Lineage differentiation is a continuous process during which fated progenitor cells execute specific programs to produce mature counterparts. This lineage-restricted pathway can be controlled by particular regulators, which are usually exclusively expressed in certain cell types or at specific differentiation stages. Here we report that miR-376a participates in the regulation of the early stages of human erythropoiesis by targeting cyclin-dependent kinase 2 (CDK2) and Argonaute 2 (Ago2). Among various human leukemia cell lines, miR-376a was only detected in K562 cells which originated from a progenitor common to the erythroid and megakaryotic lineages. Enforced expression of miR-376a or silencing of CDK2 and Ago2 by RNAi inhibits erythroid differentiation of K562 cells. Hematopoietic progenitor cells transduced with miR-376a showed a significant reduction of their erythroid clonogenic capacity. MiR-376a is relatively abundant in erythroid progenitor cells, where it reduces expression of CDK2 and maintains a low level of differentiation due to cell cycle arrest and decreased cell growth. Following erythroid induction, miR-376a is significantly down-regulated and CDK2 is released from miR-376a inhibition, thereby facilitating the escape of progenitor cells from the quiescent state into erythroid differentiation. Moreover, our results establish a functional link between miR-376a and Ago2, a key factor in miRNA biogenesis and silencing pathways with novel roles in human hematopoiesis.
authors.affiliation: Department of Biochemistry and Molecular Biology, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.forename: Gui-Hua
authors.initials: GH
authors.lastname: Yang
authors.forename: Xiao-Shuang
authors.initials: XS
authors.lastname: Wang
authors.forename: Jun-Wu
authors.initials: JW
authors.lastname: Zhang
mesh_terms: D060565:Argonaute Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000378:metabolism; D004920:Erythropoiesis; D006801:Humans; D020014:K562 Cells; D035683:MicroRNAs / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D035683:MicroRNAs; D034741:RNA, Small Interfering; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2