About Dr. Majumder
Dr. Majumder completed his predoctoral schooling at Saha Institute of Nuclear Physics in India and received his Ph.D. from New York University. He subsequently completed his postdoctoral training at Sloan Kettering Cancer Center and at Roche Institute of Molecular Biology. He joined The University of Texas M. D. Anderson Cancer Center in 1995 as an Assistant Professor and was promoted to his current position as Professor in 2006. His current research involves deciphering the mechanisms that control normal brain functions and how aberrations in these mechanisms causes diseased states such as cancer and neurodegenerative disorders. Dr. Majumder has a strong interest in teaching. In addition to leading a lab with undergraduate, graduate, postdoctoral and clinical fellows, he teaches at the Graduate School of Biomedical Sciences and organizes a biennial course at Cold Spring Harbor Laboratories on Brain Tumors. Dr. Majumder has received many awards including M. D. Anderson Fort Worth Living Legend Faculty Achievement Award, National Brain Tumor Society Chaiken Chair of Research Award, and B*CURED Research Award.
Research InterestsMechanisms of normal development and diseased states in mammalian brain
The research in my laboratory is focused on (1) deciphering the mechanisms that control normal development, (2) learning how aberrations in these mechanisms produces diseased states, and (3) investigating how such knowledge can be translated into improved patient care. In general, we begin by studying biological mechanisms and then build on the lessons learned from those studies using multiple methods including genomics, bioinformatics, biochemistry, cell biology, and mouse genetics. Our work involves close collaboration between basic scientists and clinicians.
One of the first projects in my laboratory focused on advancing understanding of the childhood brain tumor medulloblastoma (MB) as a foundation for patient-specific therapeutic approaches. In the course of our early work, we discovered that the transcriptional repressor REST is aberrantly overexpressed in a subclass of MB tumors and that a unique role of REST in these MB tumors is to block differentiation of the cerebellar stem/progenitor cells. This work was exciting because we, using REST-VP16, and others, using HDAC- and DNMT1-inhibitors, could block REST function. Our work then evolved into an investigation of the mechanisms of stemness in neural stem cells, muscle progenitor cells, embryonic stem cells, and glioblastoma stem cells. Based on our understanding of these mechanisms, in one line of work, we converted muscle progenitor cells into functional neurons before the iPS system was published. Another line of work resolved some of the contradictions in the literature and showed that the REST-mediated regulation of ES cell pluripotency through a microRNA-mediated pathway depends on the cell type (not all ES lines are the same) as well as the culture conditions, indicating how various factors form part of an interconnected regulatory network. In a third line of work, we discovered that REST regulates glioblastoma (GBM) stem cell tumorigenicity by maintaining self-renewal and invasion. Importantly, high levels of REST characterize a class of human GBM patient tumors. Our recent genome-wide analysis followed by biochemical validation indicated that REST performs its functions in GSCs through a microRNA pathway (miR-124, a known REST target, and miR-203, a new target). In addition, using such genome-wide analyses, we discovered a new mechanism (miR-21-Sox2 regulatory axis)-based GBM patient classification with implications for precision medicine. We found that this classification identifies a distinct population of glioblastoma patients with distinguishable phenotypic characteristics and clinical outcomes. In yet another line of work, we generated conditional REST overexpression knockin mice to study REST function in the brain under physiological conditions. While studying the behavior of these mice, we found evidence suggesting that REST affects neurological and neuropsychiatric functions. We are currently using multiple methods to elucidate the role of REST in tumorigenesis and in neurological/neuropsychiatric conditions, and to examine implications for therapy.
Professor and Deputy Chair, Department of Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX
Professor, Department of Neuro-Oncology, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX
Professor, The University of Texas M.D. Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX
The research in my laboratory is focused on (1) deciphering the mechanisms that control normal development of the brain and how aberrations of such mechanisms produce diseases, and (2) investigating how such knowledge can be translated into improved patient care. We begin by studying molecular mechanisms and then build on the lessons learned from those studies using a multi-disciplinary approach that encompasses genomics, bioinformatics, biochemistry, cell biology and mouse genetics. Our work involves close collaboration between basic scientists and clinicians. One of the first projects in my laboratory focused on advancing understanding of the childhood brain tumor medulloblastoma (MB) as a foundation for patient-specific therapeutic approaches. In the course of our early work, we discovered that the transcriptional repressor REST has a new function in that it maintains self-renewal and blocks differentiation of normal neural stem cells. REST is aberrantly overexpressed in a subclass of MB tumors, and a unique role of REST in these MB tumors is to block differentiation and maintain stemness of the cerebellar stem/progenitor cells. This work was exciting because we and others suggested that REST inhibitors could be utilized to block MB. Additional work suggested that REST cooperates with cMYC to form this unique subgroup of MB (High REST, High cMYC MB; HRHMMB). We are currently generating a genetically engineered mouse model of this MB subgroup. We were one of the first to show muscle progenitor cells (mesodermal lineage) can be reprogrammed by a genome-wide transcriptomic shift into a physiologically active neuronal phenotype (ectodermal lineage) by simply activating REST target genes with a single recombinant transcription factor. Although not universally accepted in 2003-2004, our studies provided some of the earliest evidence that cells are more flexible than was previously thought: cell fates can be switched by simple manipulation of a few transcription factors. Later elegant studies from several laboratories have shown that mouse and human fibroblasts can be reprogrammed to an induced-pluripotent state (iPS) by the transfer of a few transcription factors and that these iPS cells can then be differentiated into various cell-types, supporting our original findings. These studies have far-reaching implications in stem cell biology and human health. We discovered that REST maintains pluripotency of embryonic stem cells by maintaining the expression of the known pluripotency regulators, including Oct4, Nanog, and Sox2, through a novel microRNA-mediated mechanism. Our further work results resolved some of the contradictions in the literature and showed that the REST-mediated regulation of ES cell pluripotency depends on the cell-type (not all ES lines are the same) as well as the culture conditions, indicating how various factors form part of an interconnected genome-wide network influencing each other. More recently, we were also the first to show a REST-mediated regulation of oncogenic properties of glioblastoma stem cells via maintenance of stemness. Using bioinformatics and biochemical validations, we recently found a new mechanism with implications in Personalized Medicine. We found that the stemness regulator Sox2 is a new, clinically important target of microRNA-21 (miR-21) in patient glioblastoma tumors, with implications for prognosis. Using the miR-21-Sox2 regulatory axis, glioblastoma tumors can be classified into “stem-like” versus “neuronal progenitor-like” subtypes. The miR-21-Sox2 axis was also found in mouse neural stem cells and in the mouse brain at different developmental stages, suggesting a role in normal development. Importantly, this classification is a better predictor of patient survival than currently used parameters. Thus, this mechanism-based classification identifies a distinct population of glioblastoma patients with distinguishable phenotypic characteristics and clinical outcomes. In addition, we recently discovered two new mechanisms in glioblastoma. First, using genome-wide expression analysis followed by biochemical validations, we found that a new REST target in patient glioblastoma tumor-derived stem cells (GSCs) is miR-203, and that the REST-miR-203 axis specifically regulates invasion, and not proliferation or apoptosis. Second, REST represses a new target, the Dopamine Receptor 2 (DRD2) gene transcription to control tumorigenic properties of a subclass of GSCs. The latter project identified how REST can regulate GBM biology through neurotransmitter signaling. We are currently examining the potential use of FDA-approved drugs in this class of GBM tumors. I began my independent laboratory with two projects, the MB project described above, and a second project focused on determining how chromatin states regulate transcription at the beginning of mammalian development. By modifying chromatin through histone manipulation in mouse 1-cell and 2-cell embryos, we discovered that the chromatin regulation of transcription begins at the 2-cell stage of development, coinciding with the onset of zygotic transcription. Further, this function requires a unique coactivator activity. This was an exciting finding, but at the same time, we also discovered the important role of REST in MB. Because the latter discovery had potential relevance to MB patient care, we redeployed all our lab resources to that project. Recently, our work on REST in normal mice came full circle. Although REST overexpression (OE) has been implicated in many diseases and behavioral disorders, there has been a critical lack of a conditional REST OE mouse model creating a roadblock to mechanistically study the role of REST OE in these disorders under physiological conditions. To this end, we became involved in addressing this problem. We have now created the first conditional REST OE knockin mouse line. Our published results confirm that tissue-specific REST OE in these mice is physiologically relevant. Genome-wide analyses followed by biochemical and behavioral assays indicated that REST regulates spontaneous locomotion by repressing a new target, Dopamine Receptor 2. In another line of work and in collaboration with Hui-Lin Pan, we discovered that REST regulates chronic pain after nerve injury. We are currently working to decipher these mechanisms.
|1985||New York University, New York, NY, USA, PHD, Microbiology|
|1988-1992||Research Associate, Enhancer Function in Mice, Roche Institute of Molecular Biology, Nutley, NJ|
|1985-1988||Exxon Postdoctoral Fellow, Protein Kinases, Memorial Sloan-Kettering Cancer Center, New York, NY|
Associate Professor, Department of Molecular Genetics/Cancer Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 2000 - 2006
Associate Professor, Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 2000 - 2006
Assistant Professor, Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 1995 - 2000
Institute Fellow, Roche Institute of Molecular Biology, Hoffmann La-Roche, Nutley, NJ, 1992 - 1995
Teaching Assistant, Graduate Microbiology, New York University Medical School, New York, NY, 1982 - 1983
Teaching Assistant, Undergraduate Biology, New York University, New York, NY, 1979 - 1981
- Marisetty AL, Singh SK, Nguyen TN, Coarfa C, Liu B, Majumder S. REST represses miR-124 and miR-203 to regulate distinct oncogenic properties of glioblastoma stem cells. Neuro Oncol 19(4):514-523, 2017. PMID: 28040710.
- Sathyan P, Zinn PO, Marisetty AL, Liu B, Kamal MM, Singh SK, Bady P, Lu L, Wani KM, Veo BL, Gumin J, Kassem DH, Robinson F, Weng C, Baladandayuthapani V, Suki D, Colman H, Bhat KP, Sulman EP, Aldape K, Colen RR, Verhaak RG, Lu Z, Fuller GN, Huang S, Lang FF, Sawaya R, Hegi M, Majumder S. Mir-21-Sox2 Axis Delineates Glioblastoma Subtypes with Prognostic Impact. J Neurosci 35(45):15097-112, 2015. PMID: 26558781.
- Kamal MM, Sathyan P, Singh SK, Zinn PO, Marisetty AL, Liang S, Gumin J, El-Mesallamy HO, Suki D, Colman H, Fuller GN, Lang FF, Majumder S. REST regulates oncogenic properties of glioblastoma stem cells. Stem Cells 30(3):405-14. doi:10.1002/stem.1020, 2012. PMID: 22228704.
- Singh SK, Veo BL, Kagalwala MN, Shi W, Liang S, Majumder S. Dynamic status of REST in the mouse ESC pluripotency network. PLoS One 7(8):e43659. doi:10.1371/journal.pone.0043659, 2012. e-Pub 2012. PMID: 22952733.
- Gopalakrishnan V, Sinnappah-Kang N, Adams H, Fuller G, Pan ZZ, and Majumder S. Myoblast-derived neuronal cells form glutamatergic neurons in the mouse cerebellum. Stem Cells 28:1839-1847, 2010. PMID: 20799335.
- Kagalwala M, Singh S, Majumder S. Stemness is only a state of the cell. Cold Spring Harbor Laboratories Symposium on Quantitative Biology (on Stem Cells), 2009. e-Pub 2009.
- Singh S, Kagalwala M, Zhao Z, Majumder S. REST maintains self-renewal and pluripotency of embroyonic stem cells. Nature 453(7192):223-237, 2008. e-Pub 2008. PMID: 18362916.
- Su X, Gopalakrishnan V, Stearns D, Aldape K, Lang FF, Fuller G, Snyder E, Eberhart CG, Majumder S. Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation. Mol Cell Biol 26:1666-78, 2006. PMID: 16478988.
- Su X, Kameoka S, Lentz S, Majumder S. Activation of REST/NRSF target genes in neural stem cells is sufficient to cause neuronal differentiation. Mol Cell Biol 24(18):8018-25, 2004. PMID: 15340064.
- Watanabe Y, Kameoka S, Gopalakrishnan V, Aldape KD, Pan ZZ, Lang FF, Majumder S. Conversion of myoblasts to physiologically active neuronal phenotype. Genes and Development 18(8):889-900, 2004. PMID: 15078815.
- Rastelli L, Robinson K, Xu Y, Majumder S. Reconstitution of enhancer function in paternal pronuclei of one-cell mouse embryos. Mol Cell Biol 21(16):5531-40, 2001. PMID: 11463835.
- Lawinger P, Venugopal R, Guo ZS, Immaneni A, Sengupta D, Lu W, Rastelli L, Marin Dias Carneiro A, Levin V, Fuller GN, Echelard Y, Majumder S. The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells. Nature Medicine 6(7):826-31, 2000. PMID: 10888935.
- Singh SK, Marisetty A, Sathyan P, Kagalwala M, Zhao Z, Majumder S. REST-miR-21-SOX2 axis maintains pluripotency in E14Tg2a.4 embryonic stem cells. Stem Cell Res 15(2):305-311. e-Pub 2015. PMID: 26209818.