Embryonic stem cell biology and development are regulated by epigenetic mechanisms of gene expression involving chromatin modifying enzymes that promote DNA and histone modifications.  We utilize embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and mice as model systems to study how these enzymes reshape the epigenome and control gene expression programs to regulate stem cell biology and embryogenesis. The lab specializes in advanced technologies in genome editing and generating complex mouse strains. We integrate genetic, cellular, molecular, biochemical and bioinformatics approaches to dissect epigenetic pathways and mechanisms in stem cells, during development and in diseases.

The Tet family of enzymes (Tet1/2/3) modify the DNA base 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to promote DNA demethylation and gene expression. They are abundant in various cell types including the zygote, ESCs, germ cells, hematopoietic stem cells (HSCs) and neural stem cells (NSCs). Over the years, our work in the field has defined key functions of Tet enzymes in ESC differentiation, germ cell reprogramming and development (Cell Stem Cell 2011, Dev. Cell 2013, Dev. Cell 2014, Cell Reports 2019, Nucleic Acid Res. 2022, iScience 2023) as well as in hematopoiesis (Nat. Immunology 2015, Cell Reports 2015, Cell Reports 2019, Science Adv. 2022, Exp Hemaotology 2023) and in the brain (Neuron 2013, Front Cell Dev Bio 2021). Recently in my lab:

·       We have shown that the biological roles of Tet enzymes go beyond their enzymatic activity in DNA demethylation. Such non-canonical functions present a novel layer of epigenetic regulation. We study their roles in ESC pluripotency and development, as well as in hematopoietic stem cells and hematologic malignancies.

·    We have established that Tet enzymes regulate lineage specification and organogenesis. We research their biologically critical functions in post gastrulation development, in particular during embryonic hematopoiesis and neurodevelopment.

·   We study the Tet-modified base 5hmC and its derivatives 5fC and 5caC to establish their invovlements  in regulation of gene expression during development and in onset of diseases.

Our work defines how stem cell biology and development are regulated by the DNA modifying enzymes. It will unveil new mechanisms of epigenetic regulation by Tets/5hmC, and can lead to identification of unique markers and targets for stem cell applications and treatment of diseases.

For more details on our research please visit our lab website: https://www.dawlatylaboratory.com

Selected Publications:

1. Ketchum HC, Masako S, and Dawlaty MM, Catalytic-dependent and independent roles of TET3 in the regulation of specific genetic programs during neuroectoderm specification, Communications Biology, April (2024), PMID: 38580843
2. Flores JC, Sidoli S, and Dawlaty MM, Tet2 regulates Sin3a recruitment at active enhancers in embryonic stem cells, iScience, June (2023), PMID: 37456851
3. Ma L, Tang Q, Gao X, Lee J, Lei R, Suzuki M, Zheng D., Ito K, Frenette PS, and Dawlaty MM., Tet-mediated DNA demethylation regulates specification of hematopoietic stem and progenitor cells during mammalian embryogenesis, Science Advances, March (2022), PMID:35235365
4. Chrysanthou S*, Tang Q* (co-first authors), Lee J, Taylor SJ, Zhao Y, Steidl U, Zheng D, Dawlaty MM, The DNA dioxygenase Tet1 regulates H3K27 modification and embryonic stem cell biology independent of its catalytic activity, Nucleic Acid Research, February (2022), PMID:35150568
5. MacArthur I.C. and Dawlaty M.M., TET enzymes and 5-hydroxymethylcytosine in neural progenitor cell biology and neurodevelopment, Front. in Cell & Dev. Biology, February (2021) PMID: 33681230
6. Ravichandran M^*, Lei R^*(co-first author), Tang Q, Zhao Y, Lee J, Ma L, Chrysanthou S, Lorton B, Cvekl A, Shechter D, Zheng D, and Dawlaty M.M., Rinf regulates pluripotency network genes and Tet enzymes in embryonic stem cells, Cell Reports, August (2019)
7. Ito Ky^*, Lee J^*, (co-first author), Chrysanthou S, Zhao Y, Josephs K, Sato H, Teruya-Feldstein J, Zheng D, Dawlaty M.M.^** (co-corresponding author),Ito K**, Non-catalytic roles of Tet2 are essential to regulate hematopoietic stem and progenitor cell homeostasis, Cell Reports, September (2019)
8. Dawlaty M.M., Breiling A., Le T., Barrasa I.M., Raddatz G., Gao Q., Powell B.E., Cheng A.W., Faull K.F., Lyko F., and Jaenisch R., Loss of Tet enzymes compromises proper differentiation of embryonic stem cells, Developmental Cell, April (2014)
9. Dawlaty M.M., Breiling A., Le T., Raddatz G., Barrasa I.M., Cheng A.W.,Gao Q., Powell B.E., Le Z.,  Xu M., Faull K.F., Lyko F., and Jaenisch R., Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development, Developmental Cell, 24(3): 310–23 February (2013) 
10. Dawlaty M.M., Ganz K, Powell BE, Hu YC, Markoulaki S, Cheng AQ, Gao Q, Kim J, Choi SW, Page DC, and Jaenisch R. Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell, 9, 166-5, August (2011).

Additional Publications:

1. Flores JC*, Ito K* (co-first authors), Huang CY, Tang Q, Yanase C, Ito K**, Dawlaty MM**. Comparative analysis of Tet2 catalytic deficient and knockout bone marrow over time. Exp Hematol. 2023 May PMID: 37225048.
2. Chrysanthou S, Flores FC, Dawlaty MM. Tet1 Suppresses p21 to Ensure Proper Cell Cycle Progression in Embryonic Stem Cells, Cells, April (2022), PMID: 3545604
3. Abou-Jaoude A, Huang C, Flores JC, Ravichandran M, Lei R, Chrysanthou S, and Dawlaty MM. Idax and Rinf facilitate expression of Tet enzymes to promote neural and suppress trophectodermal programs during differentiation of embryonic stem cells, Stem Cell Research, March (2022), PMID:35390758
4. Aronson BE, Scourzic L, Shah V, Swanzey E, Kloetgen A, Polyzos A, Sinha A, Azziz A, Caspi I, Li J, Pelham-Webb B, Glenn RA, Vierbuchen T, Wichterle H, Tsirigos A, Dawlaty MM, Stadtfeld M, Apostolou E. A bipartite element with allele-specific functions safeguards DNA methylation imprints at the Dlk1-Dio3 locus. Developmental Cell. November (2021) PMID: 34710357
5. Bray J., Dawlaty M.M., Verma A., Maitra M., Roles and Regulations of TET enzymes in Solid Tumors, Trends in Cancer, January (2021) PMID: 33468438
6. Bhattacharyya S., Pradhan K., Campbell N., Mazdo J., Vasantkumar A., Maqbool S., Bhagat T., Gupta G., Suzuki M., Yu Y., Greally J., Steidl U., Bradner J., Dawlaty M.M., Godley L., Maitra A., Verma A. Altered Hydroxymethylation is seen at regulatory regions in pancreatic cancer and regulates oncogenic pathways, Genome Research, 2017 November 27, PMID: 28986391
7. Feng J, Pena C, Purushothaman I, Engmann O, Waker D, Issler O, Brown A, Doyle M, Harrigan E, Mouzon E, Vialou V, Shen L,Dawlaty M.M., Jaenisch R, Nestler E, Role of Tet1 in regulation of gene expression in nucleus accumbens,  Neuropsychopharmacology, 2017 January 25, PMID: 28074830
8. Yang J, Guo R, Wang H, Ye X, Zhou Z, Dan J, Wang H, Gong P, Deng W, Yin Y, Mao S, Wang L, Ding J, Li J, Keefe DL, Dawlaty M.M., Wang J, Xu G, Liu L., Tet Enzymes Regulate Telomere Maintenance and Chromosomal Stability of Mouse ESCs., Cell Reports. 2016 May 24;15(8):1809-21. PMID: 27184841
9. Zhao Z. ^*, Chen L.^*, Dawlaty M.M.^* (co-first author), Pan F., Li Z., Zhou Y., Cao Z., Shi H., Wang J., Lin L., Chen S., Weeks O., Yuan W., Qin Z, Ni H., Yang FC., Jaenisch R.**, Jin P**, Xu M**., Combined loss of Tet1 and Tet2 promotes B-cell, but not myeloid malignancies in mice, Cell Reports (2015) PMID: 26586431 PMCID: PMC4764044
10. Cimmino L.*, Dawlaty M.M.* (co-first author), Ndiaye-Lobry D., Yap Y. S., Bakogianni S., Yu Y., Bhattacharyya S., Shaknovich R., Geng H., Oricchio E., Lobry C., Mullenders J., King B., Trimarchi T., Aranda-Orgilles B., Liu C., Shen S., Wendel G., Verma A.K., Jaenisch R.**, and Aifantos I. **,Tet1 is a tumor suppressor of hematopoietic malignancy, in press Nature Immunology (2015)
11. Wiehle L., Raddatz G, Musch T., Dawlaty M.M., Jaenisch R.J., Lyko F., and Breiling A., Tet1 and Tet2 protect DNA methylation canyons against hypermethylation, Mol. Cell. Biol. (2015)
12. Theunissen T.W., Powell B.E., Wang H., Mitalipova M., Faddah D., Reddy R., Fan Z.P., Maetzel D., Ganz K., Shi L., Lungjangwa T., Imsoonthornruksa S.,Stelzer Y., Rangarajan S., D’Alessio A, Zhang J., Gao Q., Dawlaty M.M., Young R.A., Gray N.S. and Jaenisch R., Systematic Identification of Culture Conditions for Induction and Maintenance of Naive Human Pluripotency, Cell Stem Cell 15, 1–17, October (2014)
13. Rudenko A.*, Dawlaty M.M.* (co-first author), Seo J., Cheng A.W., Meng J., Le T, Faull K.F., Jaenisch R**, and Tsai L-H **,Tet1 is critical for neuronal activity-regulated gene expression and memory extinction, Neuron, 6 (79) 1109-1122, September (2013)
14. Haoyi Wang H.*, Yang H.*, Shivalila C.S.*, Dawlaty M.M., Cheng A.W., Zhang F., and Jaenisch R., One-Step Generation of Mice Carrying Mutations in Multiple Genes by CRISPR/Cas-Mediated Genome Engineering, Cell,9;153(4):910-8, May (2013)
15.  Piccolo F.M., Bagci H., Brown K., Landeira D., Soza‐Ried J., Feytout A., Moojman D., Hajkova P., Leitch H.G., Tada T., Kriaucionis S, Dawlaty M.M., Jaenisch R., Merkenschlager M. & Fisher A.G., Different roles for Tet1 and Tet2 proteins in reprogramming-mediated erasure of imprints induced by EG cell fusion, Molecular Cell 49(6):1023-33, March (2013)
16. Huang H., Jiang X., Li Z., Li Y., Song X., He C., Sun M., Chen P., Gurbuxani S., Wang J., Hong G., Elkahloun A., Arnovitz S., Wang J., Szulwach K., Lin L., Street C., Wunderlich M., Dawlaty M.M., Neilly M., Jaenisch R., Yang F., Mulloy J., Jin P., Liu P., Rowley J., Xu M., He C., and Chen J., TET1 plays an essential oncogenic role in MLL-rearranged leukemia, PNAS, USA, 110(29):11994-9 July (2013)
17. Kim JP, Su SC, Wang H, Cheng AW, Cassady JP, Lodato MA, Lengner CJ, Chung C-Y, Dawlaty M.M., Tsai L-H & Jaenisch R.  Functional integration of dopaminergic neurons directly converted from mouse fibroblasts,  Cell Stem Cell,9(5) 413-419, (2011).
18. Kim JP, Lengner CJ, Kirak O, Hanna J, Cassady JP, Lodato MA, Wu S, Faddah DA, Steine EJ, Gao Q, Fu D, Dawlaty M.M. & Jaenisch R.  Reprogramming of postnatal neurons into induced pluripotent stem cells by defined factors.  Stem Cells 29, 992-1000 (2011).
19. Staerk, J., Dawlaty, M.M., Gao, Q., Maetzel, D., Hanna, J., Sommer, C.A., Mostoslavsky, G., & Jaenisch, R.  Reprogramming of human peripheral blood cells to induced pluripotent stem cells. Cell Stem Cell, 7, 20-24 (2010).
20. Baker, D.J.*,  Dawlaty M.M.*(co-first author), Wijshake, T., Jeganathan, K. B., Malureanu, L., van Ree, J. H., Crespo-Diaz, R., S. Reyes, L. Seaburg, V. Shapiro, A. Behfar, A. Terzic, B. van de Sluis, and J.M. van Deursen. Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nature Cell Biology, 14(1), 1–9, (2012).
21. Dawlaty, M. M., Malureanu, L., Jeganathan, K. B., Kao, E., Sustmann, C., Tahk, S.,  Shuai, K., Grosschedl, R., and van Deursen, J. M., Resolution of sister centromeres requires RanBP2-mediated SUMOylation of Topoisomerase IIa. Cell 133, 103-115.  (2008).
22. Baker, D. J., Dawlaty, M. M., Galardy, P., and van Deursen J. M. , Mitotic regulation of the anaphase promoting complex (APC/C), J. M. Cell Mol Life Sci 64, 589-600 (2007).
23. Dawlaty, M. M. & van Deursen, J. M. Gene targeting methods for studying nuclear transport factors in mice. Methods 39, 370-8 (2006).