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Staff Scientist

Genomics, Development and Disease Section


B.S. California State University, 1990

Ph.D. University of California, Irvine, 1996


Dr. Stacie Loftus received her B.S. in biochemistry from California State University, Long Beach, and her Ph.D. in biological chemistry from the University of California, Irvine School of Medicine. As a graduate student in the laboratory of Dr. John Wasmuth, her dissertation detailed the identification of the gene responsible for the neural crest disorder, Treacher Collins syndrome.

Dr. Loftus came to the NIH as a postdoctoral fellow in 1996, to the National Center for Human Genome Research (NCHGR) to work as part of a collaborative team with laboratories in both NCHGR and NINDS that was focused on cloning the gene responsible for the neurodegenerative disorder Niemann-Pick disease, type C (NPC). NCHGR is now the National Human Genome Research Institute (NHGRI).

Following successful identification of the NPC1 gene, Dr. Loftus's postdoctoral work continued in the laboratory of William Pavan, Ph.D., where she integrated mouse developmental biology, gene expression profiling and genomics technologies in her work on melanocyte cell function and survival. In 2001, Dr. Loftus became an NHGRI associate investigator, where she is currently a member of the Genomics Development and Disease Section.

Her current research is focused on discovering how normal and disease melanocyte cell states establish distinct regulatory DNA landscapes, and also determining how the combination of both genetic variation within these regulatory regions and environmental cell signals alter gene expression and normal cell function.

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


Loftus SK, Morris JA, Carstea ED, Gu JZ, Cummings C, Brown A, Ellison J, Ohno K, Rosenfeld MA, Tagle DA, Pentchev PG, Pavan WJ. Murine model of Niemann-Pick C disease: Mutation in a cholesterol homeostasis gene. Science, 277:232-235. 1997. [PubMed]

Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, Gu J, Rosenfeld MA, Pavan WJ, Krizman DB, Nagle J, Polymeropoulos MH, Sturley SL, Ioannou YA, Higgins ME, Comly M, Cooney A, Brown A, Kaneski CR, Blanchette-Mackie EJ, Dwyer NK, Neufeld EB, Chang TY, Liscum L, Strauss JF, Ohno K., Zeilger M, Carmi R, Solkol J, Markie D, O'Neil RR, Van Diggelen OP, Elleder M, Patterson MC, Brady RO, Vanier MT, Pentchev PG, Tagle DA. Niemann-Pick C1 disease gene: Homology to mediators of cholesterol homeostasis. Science, 277:228-231. 1997. [PubMed]

Loftus S.K., Erikcson R.P., Walkely S.U., Bryant M.A., Incao A., Heidenreich R.A. and Pavan W.J. Rescue of neurodegeneration in Niemann Pick-C mice by a prion-promoter-driven Npc1 cDNA transgene. Hum Mol Genet, 11: 3107-3144. 2002. [PubMed]

Loftus S.K., Larson D.M., Baxter L.L., Antonellis A., Chen Y., Wu X., Bittner M, Hammer JA and Pavan WJ. Mutation of the melanosomal protein RAB38 in chocolate mice. Proc Natl Acad Sci U S A, 99:4471-4476. 2002. [PubMed]

Rao C., Foernzler D., Loftus S.K., Liu S., McPherson J.D., Jungers K.A., Apte S.S., Pavan W.J., Beier D.R.. A defect in a novel ADAMTS family member is the cause of the belted white-spotting mutation. Development, 30(19):4665-72. 2003. [PubMed]

Hou, L., Loftus, S. K., Incao, A., Chen, A., Pavan, W.J. Complementation of melanocyte development in SOX10 mutant neural crest using lineage-directed gene transfer. Dev Dyn, 229: 54-62. 2004. [PubMed]

Matera, I., Watkins-Chow, D. E., Loftus, S.K., Hou, L., Incao, A., Silver, D. L., Rivas, C., Elliott, E. C,. Baxter, L. L., Pavan, W.J. A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy. Hum Mol Genet, 17: 2118-31. 2008. [PubMed]

Buac K, Watkins-Chow DE, Loftus SK, Larson DM, Incao A, Gibney G, Pavan WJ. A Sox10 expression screen identifies an amino acid essential for Erbb3 function. PLoS Genet, 4(9). 2008. [PubMed]

Antonellis A, Huynh JL, Lee-Lin SQ, Vinton RM, Renaud G, Loftus SK, Elliot G, Wolfsberg TG, Green ED, McCallion AS, Pavan WJ. Identification of neural crest and glial enhancers at the mouse Sox10 locus through transgenesis in zebrafish. PLoS Genet, 4(9). 2008. [PubMed]

Loftus SK, Antonellis A, Matera I, Renaud G, Baxter LL, Reid D, Wolfsberg TG, Chen Y, Wang C; NISC Comparative Sequencing Program, Prasad MK, Bessling SL, McCallion AS, Green ED, Bennett DC, Pavan WJ. Gpnmb is a Melanoblast-Expressed, MITF-Dependent Gene. Pigment Cell Melanoma Res, 22(1):99-110. 2009. [PubMed]

Cronin JC, Wunderlich J, Loftus SK, Prickett TD, Wei X, Ridd K, Vemula S, Burrell AS, Agrawal NS, Lin JC, Banister CE, Buckhaults P, Rosenberg SA, Bastian BC, Pavan WJ, Samuels Y. Frequent mutations in the MITF pathway in melanoma. Pigment Cell Melanoma Res, 22:435-444. 2009. [PubMed]

Loftus SK, Baxter LL, Buac K, Watkins-Chow DE, Larson DM, Pavan WJ. Comparison of melanoblast expression patterns identifies distinct classes of genes. Pigment Cell Melanoma Res, 22:611-622. 2009. [PubMed]

Stine ZE, Huynh JL, Loftus SK, Gorkin DG, Salmasi AH, Novak T, Purves T, Miller RA, Antonellis A, Gearhart JP, Pavan WJ, McCallion AS. Oligodendroglial and Pan-neural Crest Expression of Cre Recombinase Directed by Sox10 Enhancer. Genesis, 11:765-770. 2009. [PubMed]

Prasad MK , Reed X, Gorkin DU, Cronin JC, McAdow AR, Chain K, Hodonsky CJ, Jones EA, J Svaren JP, Antonellis A, Johnson SL, Loftus SK, Pavan WJ, McCallion AS. SOX10 directly modulates ERBB3 transcription via an intronic neural crest enhancer. BMC Dev Biol, 11:40. 2011. [PubMed]

Gorkin DU, Lee D, Reed X, Fletez-Brant C, Bessling SL, Loftus SK, Beer MA, Pavan WJ, and McCallion AS. Integration of ChIP-seq and machine learning reveals enhancers and a predictive regulatory sequence vocabulary in melanocytes. Genome Res 11:2290-301, 2012. Genome Res, 11:2290-301. 2012. [PubMed]

Cronin JC, Watkins-Chow DE, Incao A, Hasskamp JH, Schönewolf N, Aoude LG, Hayward NK, Bastian BC, Dummer R,Loftus SK, Pavan WJ.SOX10 Ablation Arrests Cell Cycle, Induces Senescence, and Suppresses Melanomagenesis. Cancer Res, 73:5709-18. 2013. [PubMed]

Praetorius C, Grill C, Stacey S, Metcalf A, Robinson KC, Gorkin D, Van Otterloo E, Kim RSQ, Mishra, Davis SR, Guo T, M. Zaidi R Sigurdsson MI, Melzer PS, Merlino G, Larue L, Loftus SK, Adams DR, Pavan WJ, McCallion A, Cornell R, Smith A, Fisher DE, Sturm RA, Steingrímsson E. IRF4 affects human pigmentation by regulating expression of Tyrosinase through a MITF and TFAP2A-dependent pathway. Cell, 155:1022-33. 2013. [PubMed]

Hwang HW, Baxter LL, Loftus SK, Cronin JC, Trivedi NS, Borate B, Pavan WJ. Distinct microRNA expression signatures are associated with melanoma subtypes and are regulated by HIF1A. (2014). Distinct microRNA expression signatures are associated with melanoma subtypes and are regulated by HIF1A. Pigment Cell Melanoma Res, DOI: 10.1111/pcmr.12255. 2014. [PubMed]

Last updated: January 6, 2015