The Section on Developmental Genomics seeks to understand genomic regulation of development in health and during disease. As a first step in achieving our goal, we apply functional genomic and systems biological approaches to study gene expression and epigenomic changes that occur during development in, in vitro and in vivo models. Mouse male germ cells, at different stages of spermatogenesis, have distinct morphological features or genetic markers that allow their easy identification and preparation. Availability of cells at specific developmental stages permits the characterization of stage-specific gene expression and biological pathways. Knowledge of elements fundamental for each developmental stage will help us delineate the network of genes that regulate renewal and differentiation of spermatogonial stem cells, meiosis, and post-meiotic differentiation of germ cells, and to gain insights for development of novel methods of fertility control and aids for the infertile. Vitamin A deficiency is known to cause spermatogenic arrest at the spermatogonia stage. By studying the transcriptome of spermatogonia in the vitamin A deficient animal we hope to identify the elements that propel differentiation of these cells. Abnormalities of gene regulation during spermatogenesis lead to the development of testicular tumors. One such abnormality is the abnormal genomic methylation observed in a number of tumors. Studies of changes in the epigenome of testicular tumors will help us further understand normal genetic regulation of germ cell development. To realize the applicability of genomic approaches in clinical medicine, we applied technologies to investigate selected clinical conditions, particularly those with abnormal cell growth. One such study is of the role of mutated luteinizing hormone/chroiogonadotropin receptor (LH/hCG-R) in testicular tumor development. Another study examines the role of mitochondria in tumorigenesis.
The Section on Clinical Genomics focuses on translating genetic and genomic technologies acquired through basic studies to research on clinical problems. It has as one of its missions to provide training to physicians in the application of genomic and genetic approaches to studies of human diseases. The SCG has embarked on studying the transcription regulation of a novel testis-specific gene, mArd2, first cloned in this laboratory. The cutting-edge methylation tiling array technology is used in this investigation. Another gene actively studied is Lin 28 which has been shown to regulate developmental timing. Proteomic approaches helped the identification of RNAs bound by this protein. Gene knockdown experiments are underway to study the function of this gene in determining cell fate. Relevant to the missions of SCG is our attempt to define global approaches for the identification and screening of risk factors of complex disorders. To this end we have designed two hybridization-based high throughput methods for screening of susceptible risk factors for thrombophilia and age-related macular degeneration. Aside from basic and translational research, LCG has clinical protocols to study patients with genetic and metabolic disorders. This service gives us access to various genetic disorders and provides clinical genetics training to our fellows. This activity is viewed as a critical component of the Laboratory of Clinical Genomics.
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