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Merav Socolovsky MD, PhD

TitleProfessor
InstitutionUniversity of Massachusetts Medical School
DepartmentMolecular, Cell and Cancer Biology
AddressUniversity of Massachusetts Medical School
364 Plantation Street, LRB
Worcester MA 01605
Phone508-856-3743
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentMolecular, Cell and Cancer Biology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentCancer Biology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentImmunology and Virology

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentInterdisciplinary Graduate Program

    InstitutionUMMS - Graduate School of Biomedical Sciences
    DepartmentMD/PhD Program


    Collapse Biography 
    Collapse education and training
    University of Cambridge, Cambridge, , United KingdomBAPhysiology
    University College London, London, , United KingdomMBBSMedicine
    University of Cambridge, Cambridge, , United KingdomPHDPhysiology
    Collapse awards and honors
    1994 - 1997Howard Hughes Medical Institute Postdoctoral Fellowship for Physicians
    2002 - 2007NCI Career Development Howard Temin Award (KO1)
    2004 - 2006Charles H. Hood Foundation Child Health Research Award
    2006 - 2009American Cancer Society Research Scholar Award
    2012 - 2017Leukemia and Lymphoma Society Scholar Award
    2012Faculty Scholar Award, UMass Medical School
    2013American Society of Hematology Bridge Grant Award

    Collapse Overview 
    Collapse overview


    Visit the Socolovsky Lab website



     



    How are Red Cells Formed?



    We study mammalian red cell formation (erythropoiesis) as an accessible experimental system in which to address fundamental questions in biology and disease. Deficits in red cell formation are common worldwide, manifesting as anemia, myelodysplasia or myeloproliferative disease. The study of erythroid progenitors contributes to our understanding of these conditions. It also reveals fundamental mechanisms in lineage commitment and differentiation, relevant to oncogenesis and regenerative medicine



    Flow-cytometric analysis of erythroid progenitors



    We pioneered the use of cell-surface markers in the staging of red cell progenitors in murine blood-forming tissue (Figure 1; Socolovsky et al., Blood 2001; Zhang et al., Blood 2003; Liu et al., Blood 2006; Pop et al., PLoS Biology 2010; Koulnis et al., JoVE, 2011). This approach allows us to study minimally-perturbed primary erythroid progenitors directly within the context of their physiological niche in vivo.



     











    Socolovsky,Merav1Figure 1: Identification of erythroid progenitors and precursors within mouse fetal liver or other hematopoietic tissue using cell surface markers CD71 and Ter119. The cells can be isolated and analyzed by flow cytometry.





     



     











    SocolovskyMerav2Figure 2: Fetal liver erythroid cells are subdivided into subsets S0 to S5 containing increasingly mature erythroblasts, based on their CD71/Ter119 expression.





     



    An S-phase –dependent developmental switch activates erythroid transcription



    We found that several key committment events in early erythroid progenitors are synchronized within a single, S phase-dependent developmental switch, that takes place within S phase of a single cell cycle, at the transition from the S0 to the S1 subset (Figure 2, 3). They include a switch in chromatin configuration, activation of the erythroid master transcriptional regulator GATA-1 and the onset of dependence on erythropoietin (Epo), the principal hormonal regulator of erythropoiesis. This epigenetic switch is a new example of only a handful of known S phase-dependent developmental switches in metazoa. We are investigating the precise role of S phase in these commitment events.











    Socolovsky, Merav3Figure 3: An S –phase dependent epigenetic switch at the transition from S0 to S1: Several commitment events are synchronized in a single S phase, including dramatic changes in transcription, cell cycle regulation and chromatin.





     



    Genome-wide loss in DNA methylation during erythroid differentiation



    The erythroid S phase-dependent switch (Figure 3) is associated with a dramatic increase in the rate of DNA synthesis, apparently exceeding the DNA methylation capacity of the cells and resulting in genome-wide DNA demethylation (Figure 4,5). This global loss in methylation is required for the rapid induction of a subset of erythroid genes that are massively induced during erythropoiesis, including genes required for hemoglobin synthesis. This finding provides the first instance of a genome-wide loss in DNA methylation in normal (non-cancer) somatic cells. Previously, global demethylation was thought to be confined to the pre-implantation embryo and to primordial germ cells. We are investigating the mechanisms responsible for the global loss in DNA methylation, which may aid in understanding global demethylation in other contexts, including cancer and early development.



     











    Socolovsky, Merav4Figure 4: Red cell precursors are unusual amongst somatic (body) cells in that they undergo genome-wide loss in DNA methylation, a process that was previously thought to be confined to pluripotent cells in the early ermbryo or in the germline. Solid black circles indicates methylated CpG dinucleotides in DNA, empty circles incidate demethylated CpGs.





     



     











    Socolovsky, Merav5Figure 5: Genome-wide loss in DNA methylation. Each datapoint represents DNA methylation level in a 5kB window, sliding across the genome. Genomic DNA from increasingly mature erythroblasts (subsets S0 to S4/5) was analyzed using Reduced Representation Bisulfite Sequencing (RRBS).





     



    This work is described in the following publications:



    1. Pop,R., Shearstone, J.R., Shen, Q., Liu, Y., Hallstrom, K., Koulnis, M., Gribnau, J., Socolovsky, M. A key commitment Step in Erythropoiesis Is synchronized with the cell cycle clock Through mutual inhibition between PU.1 and S-phase progression. PLoS Biology 2010; 8(9): e1000484



    2. Shearstone, J.R., Pop, R., Bock, C., Boyle, P., Meissner, A., Socolovsky, M. Global DNA Demethylation During Erythropoiesis in vivo. Science, 2011: Vol. 334 no. 6057 pp. 799-802.





    System-level investigation of erythroblast survival



    The size of the erythroid progenitor pool determines erythropoietic rate. It may increase ten-fold in response to stress, a dynamic property of clinical importance whose regulation is incompletely understood.



    Using a combined experimental and mathematical modeling approach we found that the death receptor Fas, and its ligand, FasL, are negative regulators of erythropoiesis in the fetus and adult. Further, signaling by Epo and its receptor, EpoR, suppresses expression of the pro-apoptotic Fas, FaL and Bim proteins, and induces the anti-apoptotic Bcl-xL. These Epo-activated survival pathways appear redundant in vitro. However, we found that they each impart unique system-level functions in vivo (Figure 6). Thus, Fas and FasL are unique in that they alone amongst these proteins exert negative autoregulation of erythroblasts within erythropoietic tissue. We showed that this autoregulatory loop stabilizes the erythroid progenitor pool, and in addition, accelerates its stress response.



    By contrast, Epo-mediated induction of Bcl-xL is unique in that it undergoes classical adaptation, a dynamic response that is well known in sensory pathways or bacterial chemotaxis. Thus, the acute onset of erythropoietic stress induces a rapid but transient Bcl-xL response that quickly resets, ready to respond afresh to any further change in stress. Adaptation in the Bcl-xL pathway extends the dynamic range of the erythropoietic stress response.



     











    Socolovsky, Merav6Figure 6: In response to an increase in Epo during hypoxia stress, the EpoR in early erythroblasts transduces both a rapid, adapting survival signal via Bcl-xL induction, and a slower persistent survival signal through Bim, Fas and FasL suppression.





     





    This work is described in the following publications:



    1. Liu, Y., Pop, R., Sadegh, C., Brugnara, C., Haase, V.H., Socolovsky, M. Suppression of Fas-FasL co-expression by erythropoietin mediates erythroblast expansion during the erythropoietic stress-response in vivo. Blood, 2006; 108:123-133.



    2. Socolovsky, M*., Murrell, M., Liu, Y., Pop, R., Porpiglia, E., and Levchenko, A*. Negative Autoregulation by Fas Mediates Robust Fetal Erytrhopoiesis. PLoS Biology, 2007; 5(10): e252. *Joint corresponding authors



    This paper was highlighted in the ‘Research Roundup’ section of the Journal of Cell Biology (‘Red Blood Cells have a Killer Touch’, Robinson, R., JCB 179(2): 172 2007).



    3. Socolovsky, M. Molecular Insights into Stress Erythropoiesis. Current Opinion in Hematology, 2007,14(3):215-224.



    4. Koulnis, M., Liu, Y., Hallstrom K., Socolovsky. M. Negative autoregulation by Fas stabilizes adult erythropoiesis and Accelerates its Stress response. PLoS One. 2011;6(7):e21192.



    5. Koulnis, M., Porpiglia, E., Porpiglia, P.A., Liu, Y., Hallstrom, K., Hidalgo, D., Socolovsky, M. Contrasting Dynamic Responses in vivo of the Bcl-xL and Bim Erythropoietic Survival Pathways. Blood, 2011 Nov 15. [Epub ahead of print]. This work will be highlighted in the Cover of Blood.





     



    Collapse Rotation Projects


    Please visit the Socolovsky lab website at: http://labs.umassmed.edu/socolovskylab/ to learn about our current research areas.



    Rotation and graduate student projects are available in all areas, including:



    1. Regulation of the transition from self-renewal to differentiation in erythroid progenitors. Mouse models deleted for one or more of the relevant regulators will be analyzed.



    2. understanding the mechanism of global DNA demethylation in erythroid progenitors. Specifically, what is the role of the Tet family of proteins and 5-hydroxymethylcytosine in this process?



    3. the regulation of the erythropoietic stress response in vivo.




    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Pawaria S, Nündel K, Gao KM, Moses S, Busto P, Holt K, Sharma RB, Brehm MA, Gravallese EM, Socolovsky M, Christ A, Marshak-Rothstein A. The Role of IFN?-Producing Th1 Cells in a Type I IFN-Independent Murine Model of Autoinflammation Resulting from DNase II-Deficiency. Arthritis Rheumatol. 2019 Aug 28. PMID: 31464028.
      View in: PubMed
    2. Tusi BK, Wolock SL, Weinreb C, Hwang Y, Hidalgo D, Zilionis R, Waisman A, Huh JR, Klein AM, Socolovsky M. Population snapshots predict early haematopoietic and erythroid hierarchies. Nature. 2018 Mar 01; 555(7694):54-60. PMID: 29466336.
      View in: PubMed
    3. Weinreb C, Wolock S, Tusi BK, Socolovsky M, Klein AM. Fundamental limits on dynamic inference from single-cell snapshots. Proc Natl Acad Sci U S A. 2018 Mar 06; 115(10):E2467-E2476. PMID: 29463712.
      View in: PubMed
    4. Khoramian Tusi B, Socolovsky M. High-throughput single-cell fate potential assay of murine hematopoietic progenitors in vitro. Exp Hematol. 2018 Apr; 60:21-29.e3. PMID: 29410050.
      View in: PubMed
    5. Hwang Y, Futran M, Hidalgo D, Pop R, Iyer DR, Scully R, Rhind N, Socolovsky M. Global increase in replication fork speed during a p57KIP2-regulated erythroid cell fate switch. Sci Adv. 2017 May; 3(5):e1700298. PMID: 28560351.
      View in: PubMed
    6. Rauner M, Franke K, Murray M, Singh RP, Hiram-Bab S, Platzbecker U, Gassmann M, Socolovsky M, Neumann D, Gabet Y, Chavakis T, Hofbauer LC, Wielockx B. Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in EPO-Producing Cells. J Bone Miner Res. 2016 Oct; 31(10):1877-1887. PMID: 27082941.
      View in: PubMed
    7. Koulnis M, Porpiglia E, Hidalgo D, Socolovsky M. Erythropoiesis: from molecular pathways to system properties. Adv Exp Med Biol. 2014; 844:37-58. PMID: 25480636.
      View in: PubMed
    8. Socolovsky M. Exploring the erythroblastic island. Nat Med. 2013 Apr; 19(4):399-401. PMID: 23558622.
      View in: PubMed
    9. Porpiglia E, Hidalgo D, Koulnis M, Tzafriri AR, Socolovsky M. Stat5 signaling specifies basal versus stress erythropoietic responses through distinct binary and graded dynamic modalities. PLoS Biol. 2012 Aug; 10(8):e1001383. PMID: 22969412.
      View in: PubMed
    10. Koulnis M, Porpiglia E, Porpiglia PA, Liu Y, Hallstrom K, Hidalgo D, Socolovsky M. Contrasting dynamic responses in vivo of the Bcl-xL and Bim erythropoietic survival pathways. Blood. 2012 Feb 2; 119(5):1228-39. PMID: 22086418.
      View in: PubMed
    11. Shearstone JR, Pop R, Bock C, Boyle P, Meissner A, Socolovsky M. Global DNA demethylation during mouse erythropoiesis in vivo. Science. 2011 Nov 11; 334(6057):799-802. PMID: 22076376.
      View in: PubMed
    12. Koulnis M, Pop R, Porpiglia E, Shearstone JR, Hidalgo D, Socolovsky M. Identification and analysis of mouse erythroid progenitors using the CD71/TER119 flow-cytometric assay. J Vis Exp. 2011 Aug 05; (54). PMID: 21847081.
      View in: PubMed
    13. Koulnis M, Liu Y, Hallstrom K, Socolovsky M. Negative autoregulation by Fas stabilizes adult erythropoiesis and accelerates its stress response. PLoS One. 2011; 6(7):e21192. PMID: 21760888.
      View in: PubMed
    14. Kang BH, Xia F, Pop R, Dohi T, Socolovsky M, Altieri DC. Developmental control of apoptosis by the immunophilin aryl hydrocarbon receptor-interacting protein (AIP) involves mitochondrial import of the survivin protein. J Biol Chem. 2011 May 13; 286(19):16758-67. PMID: 21454573.
      View in: PubMed
    15. Pop R, Shearstone JR, Shen Q, Liu Y, Hallstrom K, Koulnis M, Gribnau J, Socolovsky M. A key commitment step in erythropoiesis is synchronized with the cell cycle clock through mutual inhibition between PU.1 and S-phase progression. PLoS Biol. 2010 Sep 21; 8(9). PMID: 20877475.
      View in: PubMed
    16. Lodish, H.F. Ghaffari, S. Socolovsky, M. Tong, W. Zhang, J. Intracellular signaling by the erythropoietin receptor. Book Chapter in: Erythropoietins, Erythropoietic Factors, and Erythropoiesis: Molecular, Cellular, Preclinical, and Clinical Biology. Editors: Elliott, S.G., Foote, M., Molineux, G. Birkhäuser, Basel. 2009; 155-174.
    17. Socolovsky M, Murrell M, Liu Y, Pop R, Porpiglia E, Levchenko A. Negative autoregulation by FAS mediates robust fetal erythropoiesis. PLoS Biol. 2007 Oct; 5(10):e252. PMID: 17896863.
      View in: PubMed
    18. Socolovsky M. Molecular insights into stress erythropoiesis. Curr Opin Hematol. 2007 May; 14(3):215-24. PMID: 17414210.
      View in: PubMed
    19. Liu Y, Pop R, Sadegh C, Brugnara C, Haase VH, Socolovsky M. Suppression of Fas-FasL coexpression by erythropoietin mediates erythroblast expansion during the erythropoietic stress response in vivo. Blood. 2006 Jul 1; 108(1):123-33. PMID: 16527892.
      View in: PubMed
    20. Silberstein L, Sánchez MJ, Socolovsky M, Liu Y, Hoffman G, Kinston S, Piltz S, Bowen M, Gambardella L, Green AR, Göttgens B. Transgenic analysis of the stem cell leukemia +19 stem cell enhancer in adult and embryonic hematopoietic and endothelial cells. Stem Cells. 2005 Oct; 23(9):1378-88. PMID: 16051983.
      View in: PubMed
    21. Zhang J, Socolovsky M, Gross AW, Lodish HF. Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system. Blood. 2003 Dec 1; 102(12):3938-46. PMID: 12907435.
      View in: PubMed
    22. Takahashi C, Bronson RT, Socolovsky M, Contreras B, Lee KY, Jacks T, Noda M, Kucherlapati R, Ewen ME. Rb and N-ras function together to control differentiation in the mouse. Mol Cell Biol. 2003 Aug; 23(15):5256-68. PMID: 12861012.
      View in: PubMed
    23. Brisken C, Socolovsky M, Lodish HF, Weinberg R. The signaling domain of the erythropoietin receptor rescues prolactin receptor-mutant mammary epithelium. Proc Natl Acad Sci U S A. 2002 Oct 29; 99(22):14241-5. PMID: 12381781.
      View in: PubMed
    24. Socolovsky M, Nam H, Fleming MD, Haase VH, Brugnara C, Lodish HF. Ineffective erythropoiesis in Stat5a(-/-)5b(-/-) mice due to decreased survival of early erythroblasts. Blood. 2001 Dec 1; 98(12):3261-73. PMID: 11719363.
      View in: PubMed
    25. Constantinescu SN, Keren T, Socolovsky M, Nam H, Henis YI, Lodish HF. Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain. Proc Natl Acad Sci U S A. 2001 Apr 10; 98(8):4379-84. PMID: 11296286.
      View in: PubMed
    26. Haase VH, Glickman JN, Socolovsky M, Jaenisch R. Vascular tumors in livers with targeted inactivation of the von Hippel-Lindau tumor suppressor. Proc Natl Acad Sci U S A. 2001 Feb 13; 98(4):1583-8. PMID: 11171994.
      View in: PubMed
    27. Scully R, Ganesan S, Vlasakova K, Chen J, Socolovsky M, Livingston DM. Genetic analysis of BRCA1 function in a defined tumor cell line. Mol Cell. 1999 Dec; 4(6):1093-9. PMID: 10635334.
      View in: PubMed
    28. Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF. Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction. Cell. 1999 Jul 23; 98(2):181-91. PMID: 10428030.
      View in: PubMed
    29. Socolovsky M, Fallon AE, Lodish HF. The prolactin receptor rescues EpoR-/- erythroid progenitors and replaces EpoR in a synergistic interaction with c-kit. Blood. 1998 Sep 1; 92(5):1491-6. PMID: 9716574.
      View in: PubMed
    30. Socolovsky M, Lodish HF, Daley GQ. Control of hematopoietic differentiation: lack of specificity in signaling by cytokine receptors. Proc Natl Acad Sci U S A. 1998 Jun 9; 95(12):6573-5. PMID: 9618452.
      View in: PubMed
    31. Bergelson S, Klingmüller U, Socolovsky M, Hsiao JG, Lodish HF. Tyrosine residues within the intracellular domain of the erythropoietin receptor mediate activation of AP-1 transcription factors. J Biol Chem. 1998 Jan 23; 273(4):2396-401. PMID: 9442088.
      View in: PubMed
    32. Socolovsky M, Constantinescu SN, Bergelson S, Sirotkin A, Lodish HF. Cytokines in hematopoiesis: specificity and redundancy in receptor function. Adv Protein Chem. 1998; 52:141-98. PMID: 9917920.
      View in: PubMed
    33. Socolovsky M, Dusanter-Fourt I, Lodish HF. The prolactin receptor and severely truncated erythropoietin receptors support differentiation of erythroid progenitors. J Biol Chem. 1997 May 30; 272(22):14009-12. PMID: 9162017.
      View in: PubMed
    34. Watowich SS, Wu H, Socolovsky M, Klingmuller U, Constantinescu SN, Lodish HF. Cytokine receptor signal transduction and the control of hematopoietic cell development. Annu Rev Cell Dev Biol. 1996; 12:91-128. PMID: 8970723.
      View in: PubMed
    35. Socolovsky M, Hockaday AR, Allen JM. Human high-affinity Fc IgG receptor (Fc gamma RI)-mediated phagocytosis and pinocytosis in COS cells. Eur J Cell Biol. 1994 Jun; 64(1):29-44. PMID: 7957310.
      View in: PubMed
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