Szabó
Laboratory

Overview

Developmental Reprogramming

The Szabó Laboratory studies the molecular mechanisms responsible for resetting the epigenome between generations in general and specifically in the context of genomic imprinting.

Both the soma-germline and the germline-soma transitions involve global erasure and reestablishment of DNA methylation patterns. At the soma-germline transition, the paternally and maternally inherited sets of chromosomes are prepared separately in the male and in the female germlines. The chromosomes in the sperm and egg contribute to the next generation when they join at fertilization. Soon after fertilization––at the germline-soma transition––the two half genomes undergo another wave of global remodeling initiating somatic development. The chromosomes inherited from the sperm or the egg carry with them into the soma an epigenetic memory of the male or female germlines, which is detectable in the parental-allele-specific transcription of imprinted genes.

The Szabó Laboratory is interested in the mechanisms of how DNA methylation is erased in primordial germ cells and in the zygote. We also study the patterning of de novo DNA methylation in fetal male germ cells. We use the tools of molecular biology and mouse genetics to map the changes in the epigenome and identify the specific molecules that take part in these global and imprinted locus-specific processes. In addition, we test whether the natural epigenetic reprogramming processes of the germline are sensitive to environmental insults, potentially leading to transgenerational epigenetic inheritance.

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  • 171 studies published from Nov. 1, 2020 to Oct. 1, 2021
  • 68 studies in high-impact journals from Nov. 1, 2020-Oct. 1, 2021
  • 41 clinical trials launched

Piroska Szabó, Ph.D.

Associate Professor, Department of Epigenetics

Areas of Expertise

Epigenetics, genomic imprinting, insulator, developmental reprogramming, germ line, DNA methylation, chromatin

Biography

Dr. Piroska Szabó earned an M.Sc. in biology and a Ph.D. in molecular biology from József Attila University, Szeged, Hungary. She joined Beckman Research Institute of City of Hope, Duarte, Calif. in 1992 as a postdoctoral fellow. She served first as an assistant research scientist and associate research scientist before becoming an assistant professor in the Department of Molecular and Cellular Biology at Beckman Research Institute in 2006 and was promoted to associate professor in 2011. She joined VAI in 2014 as an associate professor in the Department of Epigenetics.

SELECTED PUBLICATIONS

PubMed | Orcid

Meng Y, Wang G, He H, Lau KH, Hurt A, Bixler BJ, Parham A, Jin SG, Zu X, Vasquez KM, Pfeifer GP, Szabó PE. 2022. Z-DNA is remodelled by ZBTB43 in prospermatagonia to safeguard the germline and epigenome. Nat Cell Biol.

Zhou W, Hinoue T, Barnes B, Mitchell O, Iqbal W, Lee SM, Foy KK, Lee KH, Moyer EJ, VanderArk A, Koeman JM, Ding W, Kalkat M, Spix NJ, Eagleson B, Pospisilik JA, Szabó PE, Bartolomei M, Vander Scaaf NA, Kang L, Wiseman AK, Jones PA, Krawczyk CM, Adams M, Porecha R, Chen BH, Shen H, Laird PW. Pre-print. DNA methylation dynamics and dysregulation delineated by high-throughput profiling in the mouse. BioRxiv.

Jin SG, Meng Y, Johnson J, Szabó PE, Pfeifer GP. 2022. Concordance of hydrogen peroxide-induced 8-oxoguanine patterns with two cancer mutation signatures of upper GI tract tumorsSci Adv 8(2).

Zeng TB, Pierce N, Liao J, Singh P, Lau K, Zhou W, Szabó PE. 2022. EHMT2 suppresses the variation of transcriptional switches in the mouse embryoPLOS Genet.

Liao J, Zeng TB, Pierce N, Tran DA, Singh P, Mann JR, Szabó PE. 2021.Prenatal correction of IGF2 to rescue the growth phenotypes in mouse models of Beckwith-Wiedemann and Silver-Russell syndromes. Cell Rep 34(6):108729.

Zeng TB, Pierce N, Liao J, Singh P, Lau K, Zhou W, Szabó PE. 2021. EHMT2 suppresses the variation of transcriptional switches in the mouse embryoPLoS Genet.

Zeng, TB, Pierce N, Szabó PE. 2021. H3K9 methyltransferase EHMT2/G9a controls ERVK-driven non-canonical imprinted genesEpigenomics 13(16).

Liao J, Szabó PE. 2020. Maternal DOT1L is dispensable for mouse development. Sci Rep 10(1):20636.

Zeng TB, Szabó PE. 2020. Immunochemical detection of modified cytosine species in mammalian preimplantation embryos. Methods Mol Biol 2198:147–157.

Huang Z, Meng Y, Szabó PE, Kohli RM, Pfeifer GP. 2019. High resolution analysis of 5-hydroxymethylcytosine by TET-assisted bisulfite sequencing.Methods Mol Bio 2198:321–331.

Pfeifer GP, Szabó PE, Song J. 2019.  Protein interactions at oxidized 5-methylcytosine bases. J Mol Biol.

Zeng TB, Han L, Pierce N, Pfeifer GP, Szabó PE. 2019. EHMT2 and SETDB1 protect the maternal pronucleus from 5mC oxidationProc Natl Acad Sci U S A. 116(22):10834-10841.

Pai S, Li P, Killinger B, Marshall L, Jia P, Liao J, Petronis A, Szabó P, Labrie V. 2019. Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosisNat Comm.

Pfeifer GP, Szabó PE. 2018. Gene body profiles of 5-hydroxymethylcytosine: potential origin, function and use as a cancer biomarkerEpigenomics.

Jin SG, Zhang ZM, Dunwell TL, Harter MR, Wu X, Johnson J, Li Z, Liu J, Szabó PE, Lu Q, Xu GL, Song J, Pfeifer GP. 2016. Tet3 reads 5-carboxylcytosine through its CXXC domain and is a potential guardian against neurodegenerationCell Rep 14(3):493–505.

Szabó PE. 2015. Response to: the nature of evidence for and against epigenetic inheritanceGenome Biol 16:138

Iqbal K, Tran DA, Li AX, Warden C, Bai AY, Singh P, Wu X, Pfeifer GP, Szabó PE. 2015. Deleterious effects of endocrine disruptors are corrected in the mammalian germline by epigenome reprogrammingGenome Biol 16:59.

Hahn M, Szabó PE, Pfeifer GP. 2014. 5-hydroxymethylcytosine: a stable or transient DNA modification? Genomics 104(5):314–323.

Tran DA, Bai AY, Singh P, Wu X, Szabó PE. 2014. Characterization of the imprinting signature of mouse embryo fibroblasts by RNA deep sequencingNucleic Acids Res 42(3):1772–1783.

Liao J, He J, Szabó PE. 2013. The Pou5f1 distal enhancer is sufficient to drive Pou5f1 promoter-EGFP expression in embryonic stem cellsInt J Dev Biol 57(9-10):725–729.

Singh P, Li AX, Tran, DA, Oates N, Kang E-R, Wu X, Szabó PE. 2013. De novo DNA methylation in the male germ line occurs by default but is excluded at sites of H3K4 methylationCell Rep 4(1):205–219.

Singh P, Szabó PE. 2012. Chromatin immunoprecipitation to characterize the epigenetic profiles of imprinted domainsMethods Mol Biol 925:159–172.

Singh P, Lee DH, Szabó PE. 2012. More than insulator: multiple roles of CTCF at the H19-Igf2 imprinted domainFront Genet 3:214.

Gu TP, Guo F, Yang H, Wu HP, Xu GF, Liu W, Xie ZG, Shi L, He X, Jin SG, Iqbal K, Shi YG, Deng Z, Szabó PE, Pfeifer GP, Li J, Xu GL. 2011. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytesNature 477(7366):606–610.

Abe M, Tsai SY, Jin SG, Pfeifer GP, Szabó PE. 2011. Sex-specific dynamics of global chromatin changes in fetal mouse germ cellsPLoS One 6(8):e23848.

Kang ER, Iqbal K, Tran DA, Rivas GE, Singh P, Pfeifer GP, Szabó PE. 2011. Effects of endocrine disruptors on imprinted gene expression in the mouse embryoEpigenetics 6(7):937–950.

Iqbal K, Jin SG, Pfeifer GP*, Szabó PE*. 2011. Reprogramming of the paternal genome upon fertilization involves genome-wide oxidation of 5-methylcytosineProc Natl Acad Sci USA 108(9):3642–3647.
*Equally contributing authors

Singh P, Wu X, Lee DH, Li AX, Rauch TA, Pfeifer GP, Mann JR, Szabó PE. 2011. Chromosome-wide analysis of parental allele-specific chromatin and DNA methylationMol Cell Biol 31(8):1757–1770.
MCB Spotlight article

Lee DH, Tran D, Singh P, Oates N, Rivas GE, Larson GP, Pfeifer GP, Szabó PE. 2011. MIRA-SNuPE, a quantitative, multiplex method for measuring allele-specific DNAEpigenetics 6(2):212–223.

Lee DH, Singh P, Tsai, SY, Oates, N, Spalla A, Spalla C, Brown L, Rivas G, Larson G, Rauch AT, Pfeifer GP, Szabó PE. 2010. CTCF-dependent chromatin bias constitutes transient epigenetic memory of the mother at the H19-Igf2 imprinting control region in prospermatogoniaPLoS Genet 6(11):e1001224.

Lee DH, Singh P, Tsark WM, Szabó PE. 2010. Complete biallelic insulation at the H19/Igf2 imprinting control region position results in fetal growth retardation and perinatal lethalityPLoS One 5(9):e12630.

Singh P, Cho J, Tsai SY, Rivas GE, Larson GP, Szabó PE. 2010. Coordinated allele specific histone acetylation at the differentially methylated regions of imprinted genesNucleic Acids Res 38(22):7974–7990.

Singh P, Han L, Rivas GE, Lee DH, Nicholson TB, Larson GP, Chen T, Szabó PE. 2010. Allele-specific H3K79 Di- versus trimethylation distinguishes opposite parental alleles at imprinted regionsMol Cell Biol 30(11):2693–2707.
MCB Spotlight article

Han L, Lee DH, Szabó PE. 2008. CTCF is the master organizer of domain-wide allele-specific chromatin at the H19/Igf2 imprinted regionMol Cell Biol 28(3):1124–1135.

Szabó PE, Han L, Hyo-Jung J, Mann JR. 2006. Mutagenesis in mice of nuclear hormone receptor binding sites in the Igf2/H19 imprinting control regionCytogenet Genome Res 113(1-4):238–246.

Szabó PE, Pfeifer GP, Mann JR. 2004. Parent-of-origin-specific binding of nuclear hormone receptor complexes in the H19-Igf2 imprinting control regionMol Cell Biol 24(11):4858–4868.

Szabó PE, Tang SH, Silva FJ, Tsark WM, Mann JR. 2004. Role of CTCF binding sites in the Igf2/H19 imprinting control regionMol Cell Biol 24(11):4791–4800.

Szabó PE, Hübner K, Schöler H, and Mann JR. 2002. Allele-specific expression of imprinted genes in mouse migratory primordial germ cellsMech Dev115(1-2):157–160.

Szabó PE, Tang SH, Reed MR, Silva FJ, Tsark WM, Mann JR. 2002. The chicken beta-globin insulator element conveys chromatin boundary activity but not imprinting at the Igf2 and H19 imprinted domainDevelopment 129(4):897–904.

Szabó PE, Pfeifer GP, Miao F, O’Connor TR, Mann JR. 2000. Improved in vivo dimethyl sulfate footprinting using AlkA protein: DNA-protein interactions at the mouse H19 gene promoter in primary embryo fibroblastsAnal Biochem 283(1):112–116.

Szabó PE, Tang SH, Rentsendorj A, Pfeifer GP, Mann JR. 2000. Maternal-specific footprints at putative CTCF sites in the H19 imprinting control region give evidence for insulator functionCurr Biol 10(10):607–610.

Szabó PE, Pfeifer GP, Mann JR. 1998. Characterization of novel parent-specific epigenetic modifications upstream of the imprinted mouse H19 geneMol Cell Biol 18(11):6767–6776.

Szabó PE, Mann JR. 1996. Maternal and paternal genomes function independently in mouse ova in establishing expression of the imprinted genes Snrpn and Igf2r: no evidence for allelic trans-sensing and counting mechanismsEMBO J 15(22):6018–6025.

Szabó PE, Mann JR. 1995. Allele-specific expression and total expression levels of imprinted genes during early mouse development: implications for imprinting mechanismsGenes Dev 9(24):3097–3108.

Szabó PE, Mann JR. 1995. Biallelic expression of imprinted genes in the mouse germline: implications for erasure, establishment, and mechanisms of genomic imprintingGenes Dev 9(15):1857–1868.

Szabó P, Moitra J, Rencendorj A, Rákhely G, Rauch T, Kiss I. 1995. Identification of a nuclear factor-I family protein-binding site in the silencer region of the cartilage matrix protein geneJ Biol Chem 270(17):10212–10221.

Szabó P, Mann JR. 1994. Expression and methylation of imprinted genes during in vitro differentiation of mouse parthenogenetic and androgenetic embryonic stem cell linesDevelopment 120(6):1651–1660.

Kiss I, Bösze Z, Szabó P, Altanchimeg R, Barta E, Deák F. 1990. Identification of positive and negative regulatory regions controlling expression of the cartilage matrix protein geneMol Cell Biol 10(5):2432–2436.

Ji Liao, Ph.D.

Lab Manager

Yingying Meng

Yingying Meng, Ph.D.

Postdoctoral Fellow

How proteins safeguard genetic integrity of the species by directly binding to PPRs and eliminating Z-DNA structure in the germ cells

Amy Nuffesse

Senior Administrative Assistant II

Lab Alumni

Nick Pierce, M.S.

Research Data Technician

Tie-Bo Zheng, Ph.D.

Research Scientist