|Address:||Kaul Human Genetics Building
720 South 20th Street
Birmingham, AL 35294-0024
Lab Research Focus: Developmental Regulation of Gene Expression
The major interest of my laboratory is the regulation of gene expression during development. We study the human hemoglobin genes as a model system and translate our understanding of basic mechanisms of globin gene regulation into strategies to correct hemoglobinopathies such as beta-thalassemia and sickle cell disease.
Our work focuses on the following 4 areas:
(1) Globin gene switching during development
(2) Locus Control Region regulation of chromatin structure and gene expression
(3) Genetic modifiers of sickle cell disease severity and
(4) Genetic therapies to correct beta-thalassemia and sickle cell disease.
Our goals are to define the basic mechanisms that control globin gene regulation and to use these discoveries to develop novel strategies to cure hemoglobinopathies. Most of our studies involve the production of transgenic, knockout and knockin mice that enable us to define mechanisms of globin gene regulation and disease progression in vivo.
Some of the accomplishments of my graduate students, postdoctoral fellows and collaborators are as follows:
(1) the first transgenic mice that express a correctly regulated human gene
(2) the competition model of human hemoglobin switching during development
(3) the first mice that express functional human hemoglobin A and S
(4) the first knockout mouse model of beta-thalassemia
(5) the first mouse model of sickle cell disease.
(6) the first correction of a disease utilizing induced pluripotent stem cells (iPS cells) (collaboration with Jacob Hanna and Rudolf Jaenisch at MIT)
Recently, we have produced knockin mice that contain HA/FLAG tagged transcription factors to define complexes that regulate globin gene expression in vivo. We are also extending these studies to transcription factors that regulate other genes as part of a proteomics program to define protein:protein interactions. Mass spectrometry analysis and X-ray crystallography are utilized to define these structures. In summary, our lab uses biochemical, molecular biological and mouse genetics approaches to define basic mechanisms of gene regulation and to develop strategies to correct mouse models of human genetic diseases.