This article reviews the regulation of production of RBCs at several levels. We focus on the regulated expansion of burstforming unit-erythroid erythroid progenitors by glucocorticoids and other factors that occur during chronic anemia, inflammation, and other conditions of stress.We also highlight the rapid production of RBCs by the coordinated regulation of terminal proliferation and differentiation of committed erythroid colony-forming unit-erythroid progenitors by external signals, such as erythropoietin and adhesion to a fibronectin matrix. We discuss the complex intracellular networks of coordinated gene regulation by transcription factors, chromatin modifiers, and miRNAs that regulate the different stages of erythropoiesis. (Blood. 2011;118(24): 6258-6268) IntroductionIn mammals, definitive erythropoiesis first occurs in the fetal liver with progenitor cells from the yolk sac. 1 Within the fetal liver and the adult bone marrow, hematopoietic cells are formed continuously from a small population of pluripotent stem cells that generate progenitors committed to one or a few hematopoietic lineages (Figure 1). In the erythroid lineage, the earliest committed progenitors identified ex vivo are the slowly proliferating burstforming unit-erythroid (BFU-E). Early BFU-E cells divide and further differentiate through the mature BFU-E stage into rapidly dividing colony-forming unit-erythroid (CFU-E). 2 CFU-E progenitors divide 3 to 5 times over 2 to 3 days as they differentiate and undergo many substantial changes, including a decrease in cell size, chromatin condensation, and hemoglobinization, leading up to their enucleation and expulsion of other organelles. 3 In humans, the life span of RBCs is 120 days. Under normal conditions, approximately 1% of RBCs are synthesized each day but RBC production can increase substantially during times of acute or chronic stress, such as acute trauma or hemolysis. Exquisite short-term control of erythropoiesis is regulated by the kidney-derived cytokine erythropoietin (Epo), which is induced under hypoxic conditions and stimulates the terminal proliferation and differentiation of CFU-E progenitors. 4 BFU-E cells respond to many hormones in addition to Epo, including SCF, insulin like growth factor 1 (IGF-1), glucocorticoids (GCs), and IL-3, and IL-6. In cases of chronic erythroid stress, such as hemolysis, the number of CFU-E progenitors is insufficient to produce the needed RBCs, even under high Epo levels, and the body responds by producing more of these progenitors from BFU-E. 5 It is not entirely known which cells in the fetal liver or adult bone marrow produce these and other regulatory cytokines, or how they interact to regulate the division of BFU-E cells and control their self-renewal and their ability to differentiate into more mature CFU-E progenitors.At each stage of RBC production, intracellular signal transduction proteins and transcription factors activated downstream of these hormones interact with a group of DNA-binding and other transcription factors and chromati...

Mammals have two principal types of fat. White adipose tissue (WAT) primarily serves to store extra energy as triglycerides, while brown adipose tissue (BAT) is specialized to burn lipids for heat generation and energy expenditure as a defense against cold and obesity 1, 2. Recent studies demonstrate that brown adipocytes arise in vivo from a Myf5-positive, myoblastic progenitor by the action of Prdm16 (PR domain containing 16). Here, we identified a brown fat-enriched miRNA cluster, miR-193b-365, as a key regulator of brown fat development. Blocking miR-193b and/or miR-365 in primary brown preadipocytes dramatically impaired brown adipocyte adipogenesis by enhancing Runx1t1 (runt-related transcription factor 1; translocated to, 1) expression whereas myogenic markers were significantly induced. Forced expression of miR-193b and/or miR-365 in C2C12 myoblasts blocked the entire program of myogenesis, and, in adipogenic condition, miR-193b induced myoblasts to differentiate into brown adipocytes. MiR-193b-365 was upregulated by Prdm16 partially through Pparα. Our results demonstrate that miR-193b-365 serves as an essential regulator for brown fat differentiation, in part by repressing myogenesis.

It is unclear how epigenetic changes regulate the induction of erythroid-specific genes during terminal erythropoiesis. Here we use global mRNA sequencing (mRNA-seq) and chromatin immunoprecipitation coupled to high-throughput sequencing (CHIP-seq) to investigate the changes that occur in mRNA levels, RNA polymerase II (Pol II) occupancy, and multiple posttranslational histone modifications when erythroid progenitors differentiate into late erythroblasts. Among genes induced during this developmental transition, there was an increase in the occupancy of Pol II, the activation marks H3K4me2, H3K4me3, H3K9Ac, and H4K16Ac, and the elongation methylation mark H3K79me2. In contrast, genes that were repressed during differentiation showed relative decreases in H3K79me2 levels yet had levels of Pol II binding and active histone marks similar to those in erythroid progenitors. We also found that relative changes in histone modification levels, in particular, H3K79me2 and H4K16ac, were most predictive of gene expression patterns. Our results suggest that in terminal erythropoiesis both promoter and elongation-associated marks contribute to the induction of erythroid genes, whereas gene repression is marked by changes in histone modifications mediating Pol II elongation. Our data map the epigenetic landscape of terminal erythropoiesis and suggest that control of transcription elongation regulates gene expression during terminal erythroid differentiation. (Blood. 2011; 118(16):e128-e138)