Developmental hematopoiesis and stem cell biology.
Key words: Hematopoiesis, transcription factor, erythropoiesis, hemoglobin, megakaryocyte, embryonic stem cell, induced pluripotent stem cell.
Description of Research
We are a molecular hematology lab interested in how transcription factors control blood cell development. We use mutant mice, embryonic stem (ES) cells, induced pluripotent stem cells (iPSCs) and tissue culture cells to perform our studies. We are interested in how DNA binding proteins control the survival, proliferation and differentiation of hematopoietic stem and progenitor cells. Our studies are relevant to understanding both how normal blood cells form and mechanisms of leukemic transformation. Major projects in our laboratory include:
1*. We are creating and manipulating induced pluripotent stem cells (iPSCs) and human embryonic stem (ES) cells to create improved models for understanding and manipulating normal and pathological hematopoiesis.
2. The role of microRNAs in hematopoiesis. We are examining miR144/451, a microRNA locus that is expressed abundantly in red blood cell precursors. We showed that knockout of this locus inhibits red blood cell development in mice and zebrafish. We are studying the associated mechanisms by identifying functional miR144/451 target genes and their relevant pathways.
3*. The role of transcription factor GATA-1 in Down syndrome (DS) associated leukemogenesis. Acute megakaryoblastic leukemia is associated with trisomy 21 and mutations in the GATA1 gene. We are studying gene-manipulated mice and samples from Down syndrome patients to better understand how these two genetic lesions synergize in malignant transformation.
4*. We discovered alpha hemoglobin stabilizing protein (ASHP), a molecular chaperone that regulates hemoglobin production and homeostasis. We are using biochemical and biophysical approaches to understand how AHSP facilitates folding and stabilization of a globin. In related work, we are examining how developing red blood cells control hemoglobin and other proteins through protein quality control mechanisms including proteolysis, molecular chaperones and autophagy.
5*. We are performing genome-wide studies to better define how GATA-1 cooperates with cofactor proteins to modify chromatin and regulate gene expression during erythroid and megakaryocytic differentiation. This work complements our studies of Down syndrome associated leukemia, where the GATA1 gene is mutated.
* Indicates NIH funded projects.
There are many interesting rotation projects that can be discussed with Dr. Weiss.
Stella Chou: Assistant Professor
Janine D?Souza: Technician
Shilpa Gandre-Babbe: Research Associate
Loic Garcon: Visiting Professor
Eugene Khandros: MD/PhD student
Shwetha Manjunath: Technician
Vikram Paralkar: Postdoctoral Fellow
Orna Steinberg-Shemer: Postdoctoral Fellow
Chris Thom: MD/PhD student
Daniel VanDorn: Technician
Yu Yao: Technician
Duonan Yu: Scientist
Guowei Zhao: Postdoctoral Fellow
- Assistant Professor of Pediatrics at University of Pennsylvania School of Medicine (1999 – 2006)
- Professor of Pediatrics at University of Pennsylvania School of Medicine (2011 – 2014)
- Associate Professor of Pediatrics at University of Pennsylvania School of Medicine (2006 – 2011)
- M.D./Ph.D., Medicine and Human Genetics, University of Pennsylvania (1989)
- B.S., Biophysics, The Pennsylvania State University (with highest distinction) (1980)
- Nichols K E, Crispino J D, Poncz M, White J G, Orkin S H, Maris J M, Weiss M J. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1.. Nature Genetics. Vol 24(3) . 2000 Mar:266-70.
- Kihm Anthony J, Kong Yi, Hong Wei, Russell J Eric, Rouda Susan, Adachi Kazuhiko, Simon M Celeste, Blobel Gerd A, Weiss Mitchell J. An abundant erythroid protein that stabilizes free alpha-haemoglobin.. Nature. Vol 417(6890) . 2002 Jun:758-63.
- Weiss Mitchell J, dos Santos Camila O. Chaperoning erythropoiesis.. Blood. Vol 113(10) . 2009 Mar:2136-44.
- Maeda Takahiro, Ito Keisuke, Merghoub Taha, Poliseno Laura, Hobbs Robin M, Wang Guocan, Dong Lin, Maeda Manami, Dore Louis C, Zelent Arthur, Luzzatto Lucio, Teruya-Feldstein Julie, Weiss Mitchell J, Pandolfi Pier Paolo. LRF is an essential downstream target of GATA1 in erythroid development and regulates BIM-dependent apoptosis.. Developmental Cell. Vol 17(4) . 2009 Oct:527-40.
- Yu Ming, Riva Laura, Xie Huafeng, Schindler Yocheved, Moran Tyler B, Cheng Yong, Yu Duonan, Hardison Ross, Weiss Mitchell J, Orkin Stuart H, Bernstein Bradley E, Fraenkel Ernest, Cantor Alan B. Insights into GATA-1-mediated gene activation versus repression via genome-wide chromatin occupancy analysis.. Molecular Cell. Vol 36(4) . 2009 Nov:682-95.
- Chou ST, Khandros E, Bailey LC, Nichols KE, Vakoc C, Yao Y, Huang Z, Crispino JD, Hardison RC, Blobel GA, Weiss MJ. Graded repression of PU.1/Sfpi1 gene transcription by GATA factors regulates hematopoietic cell fate.. Blood. Vol 114(5) . 2009 Jun:983-94.
- Cheng Yong, Wu Weisheng, Kumar Swathi Ashok, Yu Duonan, Deng Wulan, Tripic Tamara, King David C, Chen Kuan-Bei, Zhang Ying, Drautz Daniela, Giardine Belinda, Schuster Stephan C, Miller Webb, Chiaromonte Francesca, Zhang Yu, Blobel Gerd A, Weiss Mitchell J, Hardison Ross C. Erythroid GATA1 function revealed by genome-wide analysis of transcription factor occupancy, histone modifications, and mRNA expression.. Genome Research. Vol 19(12) . 2009 Dec:2172-84.
- Yu Duonan, dos Santos Camila O, Zhao Guowei, Jiang Jing, Amigo Julio D, Khandros Eugene, Dore Louis C, Yao Yu, D'Souza Janine, Zhang Zhe, Ghaffari Saghi, Choi John, Friend Sherree, Tong Wei, Orange Jordan S, Paw Barry H, Weiss Mitchell J. miR-451 protects against erythroid oxidant stress by repressing 14-3-3zeta.. Genes & Development. Vol 24(15) . 2010 Aug:1620-33.