This proposal is designed to provide the Principal Investigator, Kai-Hsin Chang, with a training experience in the fields of molecular biology to expand the characterization of the commitment and differentiation of hematopoietic/erythroid cells from human embryonic stem cells (hESCs) and to study the expression of beta- locus globin genes at both cellular and molecular levels. The proposed studies are based on the observation that while hESCs can be induced to undergo hematopoietic and erythroid differentiation to help delineate the mechanisms underlying early events of hematopoiesis, the efficiency of generating hematopoietic/erythroid progenitors is low. Furthermore, unlike their fetal liver counterparts that mainly express fetal gamma globin, hESC-derived fetal-like definitive erythroid cells coexpress high levels of embryonic (epsilon) and fetal (gamma) globins with little adult beta globin. Thus, hESC-derived erythroid cells represent a valuable tool to study the activation and silencing of the beta-locus globin genes. The following specific aims are proposed: 1) To study the effect of ectopic expression of homeobox (Hox) transcription factor HoxB4 on the hematopoietic/erythroid differentiation of hESCs. 2) To characterize the cis- and trans-acting elements associated with the unique beta-locus globin expression pattern of hESC-derived erythroid cells. 3) To study the modulation of beta-locus globin gene expression by manipulation of intracellular transcriptional environment via cell fusion. While the applicant's short-term goal is to learn the molecular techniques to investigate hematopoietic/erythropoietic differentiation of hESCs and to study the regulatory mechanisms governing the globin expression. Her long-term goal is to develop an independent research program devoted to the study of erythroid cells, which will contribute to the development of althernative therapy for treating hemoglobinpathies. Dr. Thalia Papayannopoulou's laboratory has an outstanding record of studying the globin regulation using cellular and molecular approaches and thus will provide the applicant with an appropriate and stimulating teaching environment. The applicant will also benefit from the expertise of several other investigators nearby, including Dr. George Stamatoyannopoulos, the co-mentor, and Drs. David Russell, and Xiangdong Fang, the advisory committee members, necessary to accomplish the goal of present application and future objectives.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Scientist Development Award - Research & Training (K01)
Project #
Application #
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Bishop, Terry Rogers
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Yang, Yadong; Wang, Hai; Chang, Kai-Hsin et al. (2013) Transcriptome dynamics during human erythroid differentiation and development. Genomics 102:431-441
Chang, Kai-Hsin; Huang, Andy; Han, Hemei et al. (2013) Transcriptional environment and chromatin architecture interplay dictates globin expression patterns of heterospecific hybrids derived from undifferentiated human embryonic stem cells or from their erythroid progeny. Exp Hematol 41:967-979.e6
Chang, Kai-Hsin; Fang, Xiangdong; Wang, Hao et al. (2013) Epigenetic modifications and chromosome conformations of the beta globin locus throughout development. Stem Cell Rev 9:397-407
Li, Li B; Chang, Kai-Hsin; Wang, Pei-Rong et al. (2012) Trisomy correction in Down syndrome induced pluripotent stem cells. Cell Stem Cell 11:615-9
Chang, Kai-Hsin; Huang, Andy; Hirata, Roli K et al. (2010) Globin phenotype of erythroid cells derived from human induced pluripotent stem cells. Blood 115:2553-4
Bonig, Halvard; Watts, Korashon L; Chang, Kai-Hsin et al. (2009) Concurrent blockade of alpha4-integrin and CXCR4 in hematopoietic stem/progenitor cell mobilization. Stem Cells 27:836-7
Jiang, Yi; Bonig, Halvard; Ulyanova, Tatiana et al. (2009) On the adaptation of endosteal stem cell niche function in response to stress. Blood 114:3773-82
Chang, Kai-Hsin; Nelson, Angelique M; Fields, Paul A et al. (2008) Diverse hematopoietic potentials of five human embryonic stem cell lines. Exp Cell Res 314:2930-40