Sankaran Laboratory



The Sankaran Lab utilizes human genetics to refine our understanding of hematopoiesis and how this process goes awry in human disease. We are particularly interested in gaining molecular insight into how hematopoietic stem and progenitor cells are able to produce red blood cells, how the hemoglobin genes are regulated during this process, and how common variation in red blood cell traits can be due to alterations in normal hematopoiesis.

Rare Genetic Variation in Erythropoiesis
We have utilized exome and genome sequencing, as well as more traditional genetic mapping approaches, to identify mutations underlying human diseases affecting red blood cell production (erythropoiesis). This has included Diamond-Blackfan anemia (DBA), a condition where there is a complete absence of erythoid progenitors without any abnormalities in other blood lineages. Approximately 60% of the mutations in DBA are found in ribosomal protein genes. We have identified the first non-ribosomal protein mutation in DBA in the key hematopoietic transcription factor, GATA1. We are currently gaining deeper insight into the pathogenesis of this disorder by performing functional studies. For example, we have recently shown that impaired production of GATA1 is a common pathogenic mechanism in this disease. In addition, we are identifying other genetic etiologies of this disorder through the use of sequencing and informatic approaches.

In addition, we have an interest in identifying other rare disorders of erythropoiesis. We have identified several causes of abnormal erythropoiesis that result in a condition known as congenital dyserythropoietic anemia. We are performing functional studies to understand how such mutations can disrupt normal erythropoiesis. This work is providing us with a refined understanding of hematopoiesis and has important implications for efforts to manipulate this process, such as through bone marrow transplantation or gene therapy.

Regulation of the Hemoglobin Genes
We identified the first specific regulator of the fetal-to-adult hemoglobin switch, BCL11A, using human genetic studies. We have gone on to identify other regulators of this process including MYB and microRNAs 15a/16-1. Our studies are now focused on gaining mechanistic insight into how this process is regulated and how proteins such as BCL11A function during this process by leveraging our expertise in human genetics with functional studies in primary human erythroid cells. Our ability to study unique experiments of nature has provided us with an opportunity to gain important insight into this problem and identify opportunities to therapeutically manipulate this process to induce fetal hemoglobin in patients with sickle cell disease and thalassemia. In addition, we are identifying other regulators of this process using the sequencing approaches discussed above.       

Common Genetic Variation in Erythropoiesis

We have used functional follow-up approaches to better understand how common genetic variation in erythroid traits affects the process of erythropoiesis. We have specifically been interested in using these studies to identify new regulators of erythropoiesis, both using detailed mechanistic and high-throughput studies. Using such approaches, we have identified cyclins D3 and A2 as key regulators of cell cycle progression during terminal erythropoiesis, which thereby regulate red cell size and number. We have also been interested in common regulatory patterns that underlie this variation. Finally, we are attempting to take advantage of the functional insight gained into normal erythropoiesis to manipulate and modulate this process.