Stacie Loftus, Ph.D.

Associate Investigator, Genetic Disease Research Branch

Scientific Summary

Dr. Loftus' research is aimed at understanding how the human genome regulates gene expression, with a focus on how this controls the cellular processes governing mammalian development. Deciphering the processes involved in regulating gene expression is not only essential for understanding normal development, but also for comprehension of the molecular changes that occur in inborn errors of embryonic development as well as in somatic mutations that lead to cancer. Although finding the gene(s) responsible and the regulatory regions that are relevant for such conditions does not automatically lead to a cure, such findings can give important clues about what is malfunctioning at the cellular level, a required step in designing therapeutic interventions.

As part of the Genomics, Development and Disease Section (GDDS), Dr. Loftus' research focus is on understanding the cellular processes regulating melanocyte function. Melanocyte cells are specialized cells that produce melanin pigment and arise from the neural crest lineage. Neural crest cells appear along the dorsal surface of the neural tube in early embryos and migrate extensively through the body. They are pluripotent, differentiating into a variety of cell types that include cells of the peripheral nervous system, cartilage, bone, and melanocytes. The melanin pigment produced by melanocytes results in the variation in hair color, skin color and pigmentation pattern observed across evolutionarily diverse animal species. In humans, melanocytes function to protect skin from damaging environmental stresses such as ultraviolet radiation exposure (UVR). Melanocytes also can acquire somatic DNA mutations during an individual's lifetime that give rise to melanoma, a highly lethal skin cancer with increasing incidence.

 Melanocytes have the capacity to respond to a diverse number of extracellular signals, including UVR, endocrine signaling cascades that occur during pregnancy, micro-environments of the stem cell hair bulge vs. differentiated hair follicle niches, and hypoxic conditions found in metastatic melanoma tumors. Melanocytes respond by altering gene transcription, and these changes in gene expression profiles result in easily quantifiable phenotypes such as modified pigment production (a hallmark of melanocyte differentiation state) and changes in morphological cell properties.  In addition, well-characterized expression profiles for melanoma cells have been identified that correlate highly proliferative cell states with increased expression for pathways regulated by the lineage-specific transcription factors SOX10 and MITF; conversely, migratory/invasive cell states have been correlated with TGFβ1 signaling pathways.  

The GDDS laboratory was responsible for first identifying the transcription factor SOX10 as a key lineage-specific regulatory factor in melanocytes that is mutated congenitally in individuals with Waardenburg syndrome IV. Subsequent work by numerous labs has discovered that individuals with SOX10 mutations exhibit a range of neurocristopathies, including region-specific loss of melanocytes, neurosensory deafness, lack of innervation of the peripheral nervous system in the gut and peripheral myelinating neuropathy. Dr. Loftus's research has gone on to detail how SOX10 and its downstream target gene MITF coordinately regulate gene expression profiles associated with melanocyte differentiation.  Furthermore, Dr. Loftus' group has demonstrated that reduced SOX10 expression in melanoma cells confers reduced cell proliferation, induces marks of cell senescence and leads to cell cycle arrest in melanoma cells.

Results from recent GWAS studies have identified over 50 distinct SNP loci associated with either pigmentation phenotypes or susceptibility to melanoma.  The majority of these polymorphisms have been found to reside in non-coding genomic regions, underscoring the importance of understanding the epigenetic and transcriptional regulatory landscape as it applies to melanocyte biology and disease. Dr. Loftus' current research integrates the identification of these types of epigenetic modifications that mark the melanocyte regulatory genomic landscape with regulatory protein and transcription factor chromatin-binding domains, thus defining groups of non-coding DNA sequences utilized in the control of melanocyte gene expression. The resulting datasets of regulatory genomic sequence will provide a valuable resource in determining how non-coding DNA sequence variation may impact an individual's capacity to drive appropriate gene expression. Ultimately, increasing our knowledge of how genomic gene expression is governed will contribute to our ability to predict both an individual's inherent disease risks and their potential to respond to therapeutic interventions when diseases arise.

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Posted: January 6, 2015