People: Jane-Jane Chen

Bio

Jane-Jane Chen was born and raised in Taiwan. She obtained her BSc from the Department of Agricultural Chemistry, National Taiwan University in 1973. She came to USA for her graduate studies and received a PhD in 1978 from the Department of Biochemistry, School of Medicine, University of Southern California. Under the mentorship of Dr. Mary Ellen Jones, Jane-Jane investigated the regulation of pyrimidine biosynthesis in mammalian cells. She had her postdoctoral training in the laboratory of Dr. Irving M. London from 1979-1987 (part-time 1981-1983, 1985-1987) at the Harvard-MIT Division of Health Sciences and Technology, MIT. She was a Research Scientist from 1987-1990 and a Principal Research Scientist from 1990-2013 at the Harvard-MIT Division of Health Sciences and Technology. Since 2013, Jane-Jane has been a Principal Research Scientist at the Institute for Medical Engineering and Science, MIT. She is an established principal investigator with continuous NIH funding over the last three decades. Research in her laboratory focused on the translational control by heme-regulated eIF2a kinase under stress conditions and during erythropoiesis under normal and pathological conditions.

Research Interests

Phosphorylation of eIF2a is an ancient and conserved mechanism for stress adaptation from yeast to human. Research of my laboratory has been centered on advancing our understandings of the regulation of erythropoiesis by iron and heme in relation to anemia and hemoglobinopathy. We focus on the heme-sensing and signaling protein, the heme-regulated inhibitor of translation (HRI, the heme-regulated eIF2a kinase). In erythroid cells, HRI phosphorylates the a subunit of eIF2 (eIF2a), which simultaneously inhibits the translation of globin mRNAs and selectively enhances the translation of activating transcription factor 4 (ATF4) mRNA to induce stress response genes.  This coordinated translational regulation is a universal hallmark across the eIF2a kinase family under various stress and is termed the integrated stress response (ISR). We have studied the biochemistry of HRI, cloned its cDNA and generated the HRI knockout mice to investigate its physiological functions during normal development and under disease states. We generated additional ISR knockout mice and employed unbiased genome-wide in vivo translation of ribosome profiling to further interrogate the roles of HRI and heme mediated translation in terminal erythropoiesis. We demonstrate that Inhibition of protein synthesis by HRI-eIF2aP is necessary to maintain protein homeostasis in both the cytoplasm and mitochondria.  Additionally, HRI-eIF2aP specifically enhances translation of ATF4 mRNA leading to the repression of mTORC1 signaling. ATF4 target genes are most highly activated during iron/heme deficiency to maintain mitochondrial function, redox homeostasis, and to enable erythroid differentiation. HRI is therefore a master translation regulator of erythropoiesis sensing intracellular heme concentrations and oxidative stress for effective erythropoiesis.

Our Research Areas encompass:

• Translational regulation in both cytoplasm and mitochondria
• Erythropoiesis, iron deficiency anemia and thalassemia
• Fetal hemoglobin induction in hemoglobinopathy
• Integrated stress signaling in gene expression for adaptation to protein homeostasis and oxidative stress
• Erythropoietin and mTORC1 signaling
• Ribosome homeostasis
• Mitochondrial stress and respiratory function

Selected Awards/Societies

• 2000-present American Society of Hematology
• 2009-2011    Member of American Society of Hematology Scientific Committee on Iron and Heme
• 1997-2001   Member of NIH Hematology-2 Study Section
• 2013-2019   NIH Molecular and Cellular Hematology Study Section Ad Hoc
• 2019            NIH Rare Disease Clinical Network (RDCRN) U54 Study Section
• 2003-2006   NSF Panelist, Biochemistry of Gene Expression
• 1990-2020   NIH NIDDK RO1 and R21 Awards
• 1989-1998   NSF Biological Sciences Research Grant Awards
• 1995   USSN 07/938,782, DNA Encoding the Heme-Regulated Eukaryotic Initiation Factor 2a Kinase
• 2002   European Patent 0658204, DNA Encoding the Heme-Regulated Eukaryotic Initiation Factor 2a Kinase