title: Repression by RB1 characterizes genes involved in the penultimate stage of erythroid development.
abstract: Retinoblastoma-1 (RB1), and the RB1-related proteins p107 and p130, are key regulators of the cell cycle. Although RB1 is required for normal erythroid development in vitro, it is largely dispensable for erythropoiesis in vivo. The modest phenotype caused by RB1 deficiency in mice raises questions about redundancy within the RB1 family, and the role of RB1 in erythroid differentiation. Here we show that RB1 is the major pocket protein that regulates terminal erythroid differentiation. Erythroid cells lacking all pocket proteins exhibit the same cell cycle defects as those deficient for RB1 alone. RB1 has broad repressive effects on gene transcription in erythroid cells. As a group, RB1-repressed genes are generally well expressed but downregulated at the final stage of erythroid development. Repression correlates with E2F binding, implicating E2Fs in the recruitment of RB1 to repressed genes. Merging differential and time-dependent changes in expression, we define a group of approximately 800 RB1-repressed genes. Bioinformatics analysis shows that this list is enriched for terms related to the cell cycle, but also for terms related to terminal differentiation. Some of these have not been previously linked to RB1. These results expand the range of processes potentially regulated by RB1, and suggest that a principal role of RB1 in development is coordinating the events required for terminal differentiation.
authors.affiliation: a Department of Biochemistry ; St. Jude Children's Research Hospital ; Memphis , TN USA.|b Current address: Cancer Biology & Genetics; Memorial Sloan-Kettering Cancer Center ; New York , NY USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.affiliation: a Department of Biochemistry ; St. Jude Children's Research Hospital ; Memphis , TN USA.|c Hartwell Center for Bioinformatics and Biotechnology; St. Jude Children's Research Hospital ; Memphis , TN USA.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Loyd
authors.affiliation: a Department of Biochemistry ; St. Jude Children's Research Hospital ; Memphis , TN USA.
authors.forename: Mindy S
authors.initials: MS
authors.lastname: Randall
authors.affiliation: c Hartwell Center for Bioinformatics and Biotechnology; St. Jude Children's Research Hospital ; Memphis , TN USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Morris
authors.affiliation: d Cell & Molecular Biology; Lindsley F. Kimball Research Institute; New York Blood Center ; New York , NY USA.
authors.forename: Jayesh G
authors.initials: JG
authors.lastname: Shah
authors.affiliation: a Department of Biochemistry ; St. Jude Children's Research Hospital ; Memphis , TN USA.|d Cell & Molecular Biology; Lindsley F. Kimball Research Institute; New York Blood Center ; New York , NY USA.|e Current address: 1735 York Ave., New York , NY USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ney
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002478:Cells, Cultured; D019295:Computational Biology; D030541:Databases, Genetic; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D041905:Erythroid Cells / Q000378:metabolism*; D004920:Erythropoiesis; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D005865:Gestational Age; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D050684:E2F Transcription Factors; C489485:Rbl1 protein, mouse; C493838:Rbl2 protein, mouse; D017467:Receptors, Erythropoietin; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130
keywords: Retinoblastoma-1 protein; cell cycle; erythroid differentiation, pocket proteins; transcription