Yvette Yien, Ph.D.

Research Interests

Iron and heme carry out redox reactions in that are essential to life in diverse processes such as respiration, oxygen transport, detoxification and maintenance of the circadian rhythm.  While iron is one of the most abundant metals on earth, iron deficiency anemia poses a formidable public health problem, afflicting 33% of the world’s population and accounting for 8.8% of the world’s total disability (Kassebaum et al., 2014).  Dysregulation of heme and iron metabolism are most commonly associated with blood disorders such as anemia and porphyria, as red cells utilize the largest quantity of iron and heme in the body to make hemoglobin.  Defects in iron metabolism cause also disorders such as defective appetite regulation, neuronal defects, respiratory defects and cardiac defects often associated with dysregulated mitochondrial function.

While heme and iron are required in all tissues, the mechanisms by which tissues couple heme synthesis and iron uptake to their specific needs are poorly understood.  We are particularly interested in investigating how specific cell types, particularly red cells, regulate substrate transport, and modulate the activities of heme synthetic enzymes in order to satisfy the cell’s needs for heme.  We also use murine and zebrafish models to investigate the roles of heme and iron in development of hematopoietic cells, liver and pancreas.

A second key interest of the lab is to identify the mechanisms by which pregnancy regulates maternal red cell development and iron metabolism.  This is an issue of major public health significance as antenatal anemia afflicts approximately 38% of the world’s pregnant women (http://data.worldbank.org/indicator/SH.PRG.ANEM).  Though nutritional iron deficiency accounts for the majority of these cases, oral iron supplementation, the most common treatment of iron deficiency anemia, paradoxically inhibits iron uptake (Moretti et al., 2015).  Our long-term goal is to identify mechanisms by which pregnant females regulate erythropoiesis and cellular iron metabolism in order to develop more targeted therapies for anemia.

The lab uses a number of different model organisms to carry out studies, namely mammalian cell culture, yeast, mouse and zebrafish.  This combination of model systems has proven powerful in interrogating gene function within a wide range of contexts, including modeling human disease in genetic models.

Current Projects

  1. Erythroid regulation of heme synthesis.
    1. A key aspect of heme synthesis is the transport of porphyrin intermediates across cellular membranes. In 2014, we showed that the mitochondrial inner membrane protein, TMEM14C, is required for transport of protoporphyrinogen IX into the mitochondrial matrix. This transport function is required for normal red cell development and heme synthesis. We are interested in further characterizing the biochemical function of TMEM14C and identifying additional porphyrin transport proteins that may regulate the rate of heme synthesis in tissue and developmental-specific contexts.
    2. Red cells utilize cell and developmental specific mechanisms to regulate the activities of heme synthetic enzymes in order to meet cellular needs for hemoglobin synthesis. We have previously shown that the ubiquitous mitochondrial protein unfoldase, CLPX, activates the rate limiting enzyme of heme synthesis, ALAS by incorporation of its cofactor, PLP. Conversely, CLPX also plays a role in regulating ALAS turnover. Using murine and erythroid cell culture models, we aim to further interrogate other roles of CLPX in heme synthesis. The long-term goal is to identify mechanisms by which mitochondrial homeostasis interacts with, and regulates heme synthesis.
  2. Regulation of organ development by heme and iron.

    Iron deficiency anemia is a formidable public health issue which affects 38% of the world’s pregnant women. Identifying how iron deficiency affects organ development in the embryo is therefore an issue of great public health significance. As genetic inactivation of iron and heme metabolism genes in the mouse results in embryonic death from anemia prior to development of many organs, our lab uses the zebrafish to study this issue. The zebrafish is uniquely suited to such studies as many of its developmental pathways are conserved across vertebrate species. The zebrafish develops externally, allowing oxygen transport by passive diffusion. Hence, zebrafish embryos can survive without blood into the window where organ development is mostly complete. Zebrafish are also optically transparent. These aspects of the zebrafish allow real-time studies of tissue and organ development that will yield valuable insights into vertebrate developmental biology. The long-term goals of these studies are: a) to identify tissue-specific developmental pathways that are heme and iron dependent, and b) to identify iron and heme-binding proteins that play key roles in organ development.
  3. Regulation of erythropoiesis and iron metabolism during pregnancy.

    Although antenatal anemia afflicts 38% of the world’s pregnant women, its genetic causes are poorly understood. Using RNAseq and flow cytometry analysis, we will characterize changes in erythropoietic development in pregnant mice and determine how the pregnant mammal adapts red cell development and iron metabolism to meet the demands of the mother and the growing fetus.

Funding

Our lab gratefully acknowledges support from the NIH/NIDDK K01DK106156.

Research Group

We are currently seeking undergraduate work-study, students and part-time technicians to assist with zebrafish husbandry and lab chores.  We are also actively recruiting undergraduate thesis students, graduate students and postdoctoral fellows.  

  • Stashanua Carter, Graduate student
  • Emily Paglione, Undergraduate student
  • Conroy Field, Technician

Selected Publications

  1. Yien YY, Nicolas G, van der Vorm L, Gouya L, Bergonia H, Kafina MD, Deybach JC, Kardon JR, Baker TA, Phillips JD, Puy H, Paw BH.  Dominant mutation in mitochondrial unfoldase CLPX results in erythropoietic protoporphyria, Proc. Natl. Acad. Sci. USA, 114(38):E8045-E8052.

    Press coverage:  AAAS Eureka Alert: “New genetic cause discovered for photosensitive blood disorder.

    Biotechniques: “A new link to an old disorder”.  https://www.biotechniques.com/news/366373
  2. Seguin A, Takahashi-Makise N, Yien YY, Huston NC, Whitman JC, Musso G, Wallace JA, Bradley T, Bergonia H, Kafina MD, Matsumoto M, Igarashi K, Phillips JD, Paw BH, Kaplan J, Ward DM (2017).  Reductions in the mitochondrial ABC transporter Abcb10 affect the transcriptional profile of heme biosynthesis genes.  J. Biol. Chem ;292(39):16284-16299.
  3. Grillo AS, SantaMaria AM, Kafina MD, Huston NC, Cioffi AG, Han M, Seo YA, Yien YY, Menon AV, Svoboda DC, Fan J, Nardone C, Hong JD, Anderson JB, Wessling-Resnick M, Kim J, Paw BH, Burke MD (2017).  Restored iron transport by a small molecule promotes gut absorption and hemoglobinization.  Science, 356(6338):608-616.
  4. Yien YY, Paw BH (2016).  A role for iron deficiency in dopaminergic neurodegeneration (Invited Commentary).  Proc. Natl. Acad. Sci. USA 113(13): 3417-3418.  PMCID:PMC4822629.
  5. Kardon JR, Yien YY, Huston N, Branco DS, Hildick-Smith GJ, Rhee KY, Paw BH, Baker TA (2015).  Mitochondrial ClpX unfoldase activates a key enzyme for heme biosynthesis and erythropoiesis.  Cell 161(4): 858-867.  PMCID: PMC4467794.
  6. Yien YY, Gnanapragasam MN, Gupta R, Rivella S, Bieker JJ (2015).  Alternative splicing of Eklf/Klf1 in primary erythroid tissues.  Exp. Hematol. 43(1): 65-70.  PMCID: PMC4268327
  7. Yien YY, Robledo RF, Schultz IJ, Takahashi-Makise N, Gwynn B, Bauer DE, Dass A, Yi G, Li L, Hildick-Smith GJ, Cooney JD, Pierce EL, Mohler K, Dailey TA, Miyata N, Kingsley PD, Garone C, Hattangadi SM, Huang H, Chen W, Keenan EM, Shah DI, Schlager TM, DiMauro S, Orkin SH, Cantor AB, Palis J, Koehler CM, Lodish HF, Kaplan J, Ward DM, Dailey HA, Phillips JD, Peters LL, Paw BH (2014).  TMEM14C is required for erythroid mitochondrial heme metabolism.  J. Clin. Invest. 124(10):4294-4304. PMCID: PMC4191016.

    Highlight:  “NIDDK February Document” featuring the paper as one of the key publications supported by the NIDDK, February 2015, page 114.
  8. Canver MC, Bauer DE, Dass A, Yien YY, Chung J, Masuda T, Maeda T, Paw BH & Orkin SH (2014).  Characterization of genomic deletion efficiency mediated by CRISPR/Cas9 in mammalian cells.  J. Biol. Chem. 289(31): 21312-21324.  PMCID: PMC4118095.

    Highlight:  Chosen by the Editors of the JBC as one of the best papers published by the JBC (21 out of >4000 published) in 2014.

Assistant Professor

Phone: (302) 831-6685

Email: yyien@udel.edu

Office: 237 Wolf Hall

Education

  • B.S. - National University of Singapore
  • Ph.D. - Icahn School of Medicine at Mount Sinai
  • Postdoc - Brigham and Women’s Hospital, Harvard Medical School