This week we profile a recent publication in Nature Communications from the lab of Dr. Vijay Sankaran
(pictured) at Boston Children’s Hospital, the Dana-Farber Cancer Institute, and the Broad Institute.
Can you provide a brief overview of your lab’s current research focus?
Our lab is interested in understanding how human genetic variation can alter the process of blood cell production or hematopoiesis both in health and disease. We are interested in the full spectrum of genetic variation impacting humans, including common and rare genetic variation.
What is the significance of the findings in this publication?
We and others have used human genetic insights to identify key factors involved in silencing the fetal hemoglobin genes. This includes our identification of BCL11A as a key regulator of fetal hemoglobin expression 13 years ago, our identification of long-range elements involved in fetal hemoglobin silencing 10 years ago, and more recent work on mutations in the promoters of the fetal hemoglobin genes from a number of groups. How these elements interact functionally has remained unknown. Unfortunately, existing cell lines do not faithfully recapitulate what is seen in vivo. Therefore, we created a system using human primary hematopoietic cells where each of these variants was recreated using genome editing either individually or in combination. In tandem with quantitative modeling, this system enabled us to gain a deeper understanding of how different individual factors involved in fetal hemoglobin silencing act together. Fetal hemoglobin is an important factor that ameliorates the severity of both sickle cell disease and thalassemia. Our initial discovery of BCL11A as a regulator of fetal hemoglobin silencing has now led to a number of ongoing clinical trials.
What are the next steps for this research?
I think there are three exciting avenues to be pursued. First, we have introduced a primary cell system for interrogating how different elements can impact fetal hemoglobin levels. As more elements and factors are identified, this system will provide an important way to interrogate both the effect of each element in primary cells and understand how these newly identified elements might relate to previously known factors. Second, our findings suggest key epistatic interactions in silencing fetal hemoglobin and we are now interested in examining human phenotypes to examine if we can detect signs of these epistatic interactions in vivo. Third, our findings emphasize the value of such reductionist experimental systems to gain insights into genetic interactions that might occur in vivo, even for other phenotypes or diseases.
