We strive to make a difference in the lives of our fellow human beings with our research, education and training programs. Interdisciplinary research in our laboratory focuses on deciphering the mechanisms that control normal neuronal development and learning how aberration of such mechanisms produces disease and other forms of dysfunction such as cancer. Equally important, we are intent on determining how such knowledge can be used to develop therapeutic approaches to these diseases and dysfunctions. We began with a focus on deciphering how epigenomic and transcriptomic regulations by REST, a transcriptional repressor, control normal neural stem cell biology and how aberrations of these mechanisms cause brain tumors. Building on the lessons learned from those studies, recently we have expanded our research to learn how REST regulates chronic pain, topics also important in cancer research. Our research involves collaboration between basic and clinical department investigators.
Working model of HRHMMB
Aberrant stemness is a mechanism in brain tumors
We discovered that REST is a regulator of tumorigenesis in a subtype of children’s brain tumors, medulloblastoma, by aberrantly maintaining stemness of cancer cells. Further, this work produced one of the first studies suggesting aberrant stemness as a mechanism in brain tumors. Although not universally accepted at that time, brain tumor cancer stem cells were later isolated by others confirming our observations. We further discovered that REST cooperates with cMYC to form a specific subtype of MB tumors. This work was exciting because we and others suggested that REST inhibitors could be utilized to block MB. We are currently working to increase understanding of the understudied High REST + High MYC MB patients.
- Lawinger, P., Venugopal, R., Guo, Z-S, Immaneni, A., Rastelli, L., Sengupta, D., Lu, W., Zhao, Z., Carneiro, A., Fuller, G., Echelard, Y., and Majumder, S. (2000) The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells. Nature Medicine 6, 826-831. PMID: 10888935
- Immaneni, A., Lawinger, P., Zhao, Z., Lu, W., Rastelli, L., Morris, J., and Majumder, S. (2000) REST-VP16 activates expression of multiple neuronal differentiation genes in NT2 cells. Nucleic Acids Research 28, 3403-3410. PMID: 10954611 PMCID: PMC110685
- Fuller, G.N., Su, X., Price, R.E., Cohen, Z.R., Lang, F.F., Sawaya, R., and Majumder, S. (2005) Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription factor (REST)/neuron-restrictive silencer factor, which can be functionally countered by REST-VP16. Molecular Cancer Therapeutics 4:343-349. PMID: 15767543
- Su, X., Gopalakrishnana, V., Stearns, D., Aldape, K., Lang, F.F., Fuller, G.N., Snyder, E., Eberhart, C., and Majumder, S. (2006) Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation. Molecular and Cellular Biology 26:1666-1678. PMID: 16478988 PMCID: PMC1430235
We then discovered that REST-mediated maintenance of aberrant stemness also occurs in patient glioblastoma (GBM) stem cells (GSCs). We found two new mechanisms that shed light on how REST does its function in GSCs. First, REST has a new target, microRNA-203, and that the REST-miR-203 axis specifically regulates invasion, and not proliferation or apoptosis. We are currently attempting to find out how this axis can be exploited to manage GBM using exosome-mediated delivery of miRNA. Second, REST represses another new target, the Dopamine Receptor 2 gene, to control tumorigenic properties of a subclass of GSCs. The latter project identified how REST can regulate GBM biology through neurotransmitters. The REST-DRD2 axis subdivided GBM tumors into High REST, Low DRD2 (HRLD) and Low REST, High DRD2 (LRHD) molecular subclasses. The Cancer Genome Atlas GBM data supported the presence of a REST-DRD2 axis and revealed that HRLD and LRHD tumors are specific subtypes, are molecularly different from the known GBM subtypes, and represent functional groups with distinctive patterns of enrichment of gene sets and biological pathways. Indeed, the inverse HRLD/LRHD expression pattern was also seen in in-house GBM tumors and in regular mice. We are currently examining the potential use of FDA-approved drugs in this class of GBM tumors.
To determine what regulates tumorigenesis in a class of GSCs that are not regulated by REST, we collaborated with others. Our results suggested that the RNA demethylase ALKBH5 maintains tumorigenicity in the non-REST GSCs. This work has started to give us information on how different mechanisms regulate tumorigenicity of different classes of GSCs.
In a different line of work, we discovered 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.
- Kamal, M. M. Sathyan, P., Singh, S. K., Zinn, P. O., Marisetty, A., Liang, S., Gumin, J., Gu, P., El-Mesallamy, H. O., Suki, D., Colman, H., Fuller, G., Lang, F. and Majumder, S. (2012) REST regulates oncogenic properties of glioblastoma stem cells. Stem Cells 30(3):405-14. doi: 10.1002/stem.1020. PMID: 22228704 PMCID: PMC4039365
- Sathyan, P., Zinn, PO., Marisetty, AL., Liu, B., Kamal, M.M., 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, RGW., Lu, Z., Fuller, GN., Huang, S., Lang, FF., Sawaya, R., Hegi, M., Majumder, S. (2015) Mir-21–Sox2 axis delineates glioblastoma subtypes with prognostic impact. J. Neuroscience 35(45):15097-112. PMID: 26558781 PMCID: PMC4642241
- Marisetty, A., Singh, S., Nguyen, T., Coarfa, C., Liu, B., and Majumder, S. (2017) REST represses miR-124 and miR-203 to regulate distinct oncogenic properties of glioblastoma stem cells. Neuro-Oncology 2017 Apr 1;19(4):514-523. PMID:28040710
- Marisetty AL, Lu L, Veo BL, Liu B, Coarfa C, Kamal MM, Kassem DH, Irshad K, Lu Y, Gumin J, Henry V, Paulucci-Holthauzen A, Rao G, Baladandayuthapani V, Lang FF, Fuller GN, Majumder S. (2019) REST-DRD2 mechanism impacts glioblastoma stem cell-mediated tumorigenesis. Neuro Oncol. 2019 Jun 10;21(6):775-785. PMID: 30953587
Conversion of muscle progenitor cells into neurons
During our earlier studies, we discovered that stem/progenitor cells are more flexible than previously thought, and this flexibility can determine both normal development and disease: conversion of myoblasts to neuronal phenotypes with a single recombinant molecule. 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.
- Watanabe, Y. Kameoka, S., Gopalakrishnan, V., Aldape, K.D., Pan, Z.Z., Lang, F.F., and Majumder, S. (2004). Conversion of myoblasts to physiologically active neuronal phenotype. Genes & Development 18: 889-900. PMID: 15078815
- Su, X., Kameoka, S., Lentz, S., and Majumder, S. (2004) Activation of REST/NRSF target genes in neural stem cells is sufficient to cause neuronal differentiation. Molecular and Cellular Biology 24: 8018-8025. PMID: 15340064
- Kagalwala MN, Singh SK, Majumder S. Stemness is only a state of the cell. Cold Spring Harb Symp Quant Biol. 2008;73:227-34. PMID: 19150961
- Gopalakrishnan, V., Bie, B., Sinnappah-Kang, N., Adams, H., Fuller, G., Pan, Z.Z., and Majumder, S. (2010) Myoblast-derived neuronal cells form glutamatergic neurons in the mouse cerebellum. Stem Cells 28:1839-1847 (2010). PMID: 20799335
Maintenance of pluripotency of mouse embryonic stem cells
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.
- Singh, SK, Kagalwala, M., Parker -Thornburg, J. Adams, H., and Majumder, S. (2008) REST maintains self-renewal and pluripotency of embryonic stem cells. Nature 453:223-227. PMID: 18362916
- Kagalwala MN, Singh SK, Majumder S. Stemness is only a state of the cell. Cold Spring Harb Symp Quant Biol. 2008;73:227-34. PMID: 19150961
- Singh, S., Veo, B., Kagalwala, M., Shi, W., Liang, S., Majumder, S. (2012) Dynamic status of REST in the mouse ESC pluripotency network. PLoS ONE 7(8): e43659. PMID: 22952733 PMCID: PMC3429488
- Singh, SK, Marisetty, A., Sathyan, P., Kagalwala, M., Zhao, Z., and Majumder, S (2015). REST-miR-21-SOX2 axis maintains pluripotency in E14Tg2a.4 embryonic stem cells. Stem Cell Research 15(2):305-311. PMID: 26209818 PMCID: PMC4654943
Mechanisms of chronic pain
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 human 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 hREST OE knockin mouse line. Our results confirm that tissue-specific REST OE in these mice is physiologically relevant. Our data suggested that REST represses a new target, Dopamine Receptor 2. Using our Rest conditional OE mouse line and a complementary Rest conditional knockout mice line, our most recent studies in collaboration with Hui-Lin Pan suggest that REST in DRG neurons is involved in neuropathic pain after nerve injury by regulating unique epigenomic and transcriptomic signatures (including mRNAs and miRs).
- Majumder, S., Z. Zhao, Kaneko, K. and M.L. DePamphilis. (1997) Developmental acquisition of enhancer function requires a unique coactivator activity EMBO J. 16: 1721-1731. PMID: 9130716
- Lawinger, P., Rastelli, L., Zhao, Z. and Majumder, S. (1999) Lack of enhancer function in mammals is unique to oocytes and fertilized eggs. J. Biol. Chem. 274: 8002-8011. PMID:10075699
- Rastelli, L., Robinson, K., Xu, Y., and Majumder, S. (2001) Reconstitution of enhancer function in paternal pronuclei of one-cell mouse embryos Mol. Cell. Biol. 21: 5531-5540. PMID: 11463835
- Lu, L., Marisetty, A., Liu, B., Kamal, M.M., Gumin, J., Veo, B., Cai, Y., Kassem, D., Weng, C., Maynard, M., Hood, K., Fuller, G., Pan, Z., Cykowski, M.D., Dash, P., and Majumder, S. (2018) REST overexpression in mice causes deficits in spontaneous locomotion. Sci Rep. 2018 Aug 14;8(1):12083 PMID: 30108242
My philosophy is that it is very important to pass the baton on to our next generation. My door is always open to trainees. I have been very active in the education and training of students, fellows, and junior faculty. My lab has trained more than 65 trainees. I am a member of the Genetics and Epigenetics Program of the University of Texas MD Anderson UT Health Houston Graduate School of Biomedical Sciences. I directed the Genes and Development graduate program from 2013-2015. I also organized courses and developed my own course on Neural Stem Cells. I am continuing to serve as a faculty advisor for the MDA T32 Training Grant, Translational Genomics and Precision Medicine. I also pursue my educational commitment beyond MDA. I created, raised money for, and organized a very successful course on Brain Tumors at the Cold Spring Harbor Laboratory. This course has been held regularly since 2006. The idea behind this course is to accelerate progress in basic and translational research. This course is distinctive not only for the high caliber of the participants and the intensity and interactive nature of the sessions, but also for its collegial spirit. Recently, I initiated the first Gordon Research Conference on Brain Tumors (2023).
If you are interested in our programs, please contact me at: firstname.lastname@example.org