Cyclin D3 coordinates the cell cycle during differentiation to regulate erythrocyte size and number

Abstract

Genome-wide association studies (GWASs) have identified a genetic variant of moderate effect size at 6p21.1 associated with erythrocyte traits in humans. We show that this variant affects an erythroid-specific enhancer of CCND3. A Ccnd3 knockout mouse phenocopies these erythroid phenotypes, with a dramatic increase in erythrocyte size and a concomitant decrease in erythrocyte number. By examining human and mouse primary erythroid cells, we demonstrate that the CCND3 gene product cyclin D3 regulates the number of cell divisions that erythroid precursors undergo during terminal differentiation, thereby controlling erythrocyte size and number. We illustrate how cell type-specific specialization can occur for general cell cycle components-a finding resulting from the biological follow-up of unbiased human genetic studies.

Transcriptional divergence and conservation of human and mouse erythropoiesis

“…At the polychromatophilic and orthochromatophilic erythroblast stages, human and mouse erythroid cells have reduced expression of CD71, but retain a high level of GlyA. Polychromatophilic and orthochromatophilic erythroblasts contain less RNA and DNA, compared with the earlier stages, and are also smaller (17).…”

Hematopoiesis specific loss of Cdk2 and Cdk4 results in increased erythrocyte size and delayed platelet recovery following stress

“…[19][20][21] Cdk6 -/-mice display enlarged erythrocyte size accompanied by a concomitant decrease in erythrocyte counts and Cdk4 -/-Cdk6 -/-mice die during late gestation due to impaired erythropoiesis. 7 Loss of cyclin D3, 18 the major cyclin partner for Cdk4/6, phenocopies the enlarged erythroid cell size observed in Cdk6 -/-and Cdk4 -/-…”

“…There were no significant alterations in levels of cyclin D3 and E2F4, proteins that have been implicated in regulating erythrocyte size. [18][19][20][21] The levels of Cdk6, cyclin E, and the Cdk inhibitor -fetal liver erythroblasts were purified from Cdk2 -/-Cdk4 -/-and littermate control (Cdk2 +/-Cdk4 +/-or Cdk2 +/+ Cdk4 +/+ ) E13.5 mouse embryos (n=4), and cultured in erythropoietin-containing medium for 12 h, followed by a 1 h BrdU pulse (10 mM). After 1 h BrdU pulsing, the cells were washed to remove the BrdU and cultured again in erythropoietin-containing medium.…”

Society for Pediatric Research 2015 Young Investigator Award: genetics of human hematopoiesis—what patients can teach us about blood cell production

“…Our focus has been on using insight from GWAS to identify regulatory elements and the genes they affect to gain new insight into hematopoiesis. For example, we identified variants altering the levels of cyclins D3 and A2, which have key roles in regulating the cell divisions that occur in the last stages of erythropoiesis before the cells prepare to enucleate and form mature RBCs (45,46). It should be noted that over 75 loci have been identified as associated with RBC and other blood cell traits (47), suggesting that there may be more opportunities to gain important new insight into regulators of erythropoiesis and hematopoiesis through more systematic studies.…”