TRIM28 is essential for erythroblast differentiation in the mouse

Abstract

Key Points• Genetic loss of the transcriptional corepressor TRIM28 in adult mice results in deficient adult erythropoiesis in bone marrow, and anemia. • TRIM28 controls the mRNA levels of multiple erythroid transcription factors, heme biosynthetic enzymes, and the apoptotic apparatus.In previous mass spectrometry and coimmune precipitation studies, we identified tripartite motif-containing 28 (TRIM28; also known as transcriptional intermediary factor1b and Krüppel-associated box-associated protein-1) as a cofactor that specifically copurified with an NR2C1/NR2C2 (TR2/TR4) orphan nuclear receptor heterodimer that previous studies had implicated as an embryonic/fetal b-type globin gene repressor. TRIM28 has been characterized as a transcriptional corepressor that can associate with many different transcription factors and can play functional roles in multiple tissues and cell types. Here, we tested the contribution of TRIM28 to globin gene regulation and erythropoiesis using a conditional loss-of-function in vivo model. We discovered that Trim28 genetic loss in the adult mouse leads to defective immature erythropoiesis in the bone marrow and consequently to anemia. We further found that TRIM28 controls erythropoiesis in a cell-autonomous manner by inducibly deleting Trim28 exclusively in hematopoietic cells. Finally, in the absence of TRIM28, we observed increased apoptosis as well as diminished expression of multiple erythroid transcription factors and heme biosynthetic enzymes in immature erythroid cells. Thus, TRIM28 is essential for the cell-autonomous development of immature erythroblasts in the bone marrow. (Blood. 2013;122(23):3798-3807)

KAP1 Represses Differentiation-Inducible Genes in Embryonic Stem Cells through Cooperative Binding with PRC1 and Derepresses Pluripotency-Associated Genes

“…KAP1 and PRC1 are required for the selfrenewal or differentiation of many classes of multipotent stem cells in mice (30)(31)(32)(33)(34)(35)(36)(37)52). Most transitions between progenitor and differentiated cell types involve the coordinated derepression of differentiation-inducible genes and the repression of progenitorspecific genes.…”

“…The fluorescence microscopy images show the subnuclear distributions of BiFC complexes formed by KAP1 with the Cbx family proteins indicated above the adjacent bar graphs. ment of many cell types in adult mice (30)(31)(32)(33)(34)(35)(36)(37)52). Many mechanisms have been proposed to mediate the effects of KAP1 and PRC1 on the proliferation and differentiation of multipotent progenitor cells.…”

Fetal Globin Gene Repressors as Drug Targets for Molecular Therapies To Treat the β-Globinopathies

“…We also previously identified TRIM28 as an interacting protein of TR2/TR4 (39). TRIM28 is dispensable for fetal globin silencing but is required for erythroid differentiation, implying that TRIM28 may function as a coactivator of TR2/TR4 (60). However, it is equally plausible that TRIM28 functions as a corepressor, as it does in other contexts (61), to inhibit the transcription of a currently unidentified activator that is required for erythroid differentiation.…”

TAF10 Interacts with the GATA1 Transcription Factor and Controls Mouse Erythropoiesis

“…CNOT3, CBX1, and TRIM28 were previously reported to form a unique module involved in developmental processes (70), and TRIM28 in particular has an important role in erythropoiesis (53,71). Of note, CNOT3 and TRIM28 do not physically interact, while there have been reports of interactions of TFIID with the CCR4-NOT complex (72).…”