Principal Investigator Harvey Lodish
In work being performed with Eric Lander and colleagues at the Broad Institute, Vijay Sankaran along with laboratory colleagues Leif Ludwig, Jenn Eng, and Evelyn Wang are dissecting the genetic architecture of human erythropoiesis. This work is being performed using a combination of complex trait genetics, Mendelian genetics, and analysis of rare human syndromes.
Elevated levels of fetal hemoglobin can ameliorate the major disorders of beta-hemoglobin, sickle cell disease and beta-thalassemia. Vijay and his colleagues had followed up on a several decades old observation that patients with trisomy 13 have elevated levels of fetal hemoglobin and used mapping of partial trisomy cases to show that microRNAs 15a and 16-1 appeared as a top candidates as mediators of this phenotype. Indeed, increased expression of these microRNAs in primary human erythroid progenitor cells resulted in elevated fetal and embryonic hemoglobin gene expression. Moreover, they showed that a direct target of these microRNAs, MYB, plays an important role in silencing the fetal and embryonic hemoglobin genes. Thus they demonstrated how the developmental regulation of a clinically important human trait can be better understood through the genetic and functional study of aneuploidy syndromes, and suggest that miR-15a, 16-1, and MYB may be important therapeutic targets to increase HbF levels in patients with sickle cell disease and β-thalassemia. Following up on this work, Leif and Vijay are defining the physiological function of these microRNAs using a variety of approaches in primary mouse and human erythroid progenitor cells. In addition, Jenn, Leif, and Vijay are following up on alternative strategies for targeting MYB and are attempting to better understand the mechanism of action by which this transcription factor is able to regulate fetal hemoglobin levels. Finally, ongoing work is aimed at understanding the mechanistic basis for alterations in hemoglobin expression in the context of other rare human syndromes.
Using complex trait genetics, Vijay, Jenn, and Leif have been defining new regulators of human erythropoiesis. By using readily-measured erythrocyte traits and following up on the results of genome-wide association studies (GWAS), new mechanisms underlying the regulation of erythropoiesis are being defined. The studies involve close collaborations with several groups in Boston and Cambridge, as well as internationally.
To gain further insight into important regulators of erythropoiesis, Vijay has been using Mendelian genetic approaches to identify genes mutated in rare human diseases with perturbations in erythropoiesis. With collaborators at a number of institutions, new candidate genes mediating these diseases have been defined and functional work is being performed to understand the nature and mechanism of action of these genes.