Epigenetic control of spermatogonial stem cells

Self-renewal of spermatogonial stem cells is vital to lifelong production of male gametes and thus fertility. However, the underlying mechanisms remain enigmatic. We have discovered that DOT1L, the sole H3K79 methyltransferase, is required for spermatogonial stem cell self-renewal. Mice lacking DOT1L fail to maintain spermatogonial stem cells, characterized by a sequential loss of germ cells from spermatogonia to spermatids and ultimately a Sertoli cell only syndrome. Inhibition of DOT1L reduces the stem cell activity after transplantation. DOT1L promotes expression of the fate-determining HoxC transcription factors in spermatogonial stem cells. Furthermore, H3K79me2 accumulates at HoxC9 and HoxC10 genes. Our findings identify an essential function for DOT1L in adult stem cells and provide an epigenetic paradigm for regulation of spermatogonial stem cells.

 

piRNAs, DNA methylation, and transposon silencing

Piwi-interacting RNAs are a diverse class of small non-coding RNAs implicated in the silencing of transposable elements and the safeguarding of genome integrity. In mammals, male germ cells express two genetically and developmentally distinct populations of piRNAs at the pre-pachytene and pachytene stages of meiosis, respectively.

Pre-pachytene piRNAs are mostly derived from retrotransposons and required for their silencing. In contrast, pachytene piRNAs originate from ~100 genomic clusters depleted of transposable elements. We find that MOV10L1, a 5' - 3' RNA helicase, is a master regulator of biogenesis of all piRNAs. Mov10l1 is one of the 36 germ cell-specific genes identified in our genomic screen. Mechanistically, MOV10L1 binds to piRNA precursors to initiate piRNA biogenesis. MOV10L1 interacts with PIWI proteins and TDRD1 and its RNA helicase activity is required to resolve the thermostable G-quadruplex secondary structures in piRNA precursors.

DNA methylation is a major silencing mechanism of transposable elements (TEs). We report that TEX15, a testis-specific protein that we previously identified, is required for TE silencing. TEX15 is expressed in embryonic germ cells and functions during genome-wide epigenetic reprogramming. The Tex15 mutant exhibits DNA hypomethylation in TEs at a level similar to Mili and Dnmt3c but not Miwi2 mutants. TEX15 is associated with MILI in testis. As loss of Tex15 causes TE desilencing with intact piRNA production, our results identify TEX15 as a new essential epigenetic regulator that may function as a nuclear effector of MILI to silence TEs by DNA methylation.

The X chromosome and Male Infertility

We have identified TEX11 as the first X chromosome-encoded meiosis-specific factor in mammals. In principle, meiosis-specific genes could be located anywhere in the genome. However, no mouse sex chromosome-linked mutants with meiosis-specific defects had been reported, leading to the perception that meiosis-specific factors are rarely if ever encoded by the sex chromosomes. We were the first to clone Tex11, an X-linked germ cell-specific gene, in our genomic screen.

In a recent study, by ablating the function of Tex11 in mice, we have demonstrated that Tex11 is essential for meiosis and fertility in males. Our findings have important implications for male infertility in humans, which accounts for about half of the cases of infertility among couples. An estimated 15% of couples are affected by infertility worldwide. Given that disruption of Tex11 causes azoospermia in mice, we surmise that mutations in the human TEX11 gene could be found in infertile men.

Regulation of Homologous Recombination

During meiosis, homologous chromosomes undergo synapsis and recombination. Meiotic recombination enables the reciprocal exchange of genetic material between parental homologous chromosomes, and ensures faithful chromosome segregation during meiosis in sexually reproducing organisms.

This process relies on the complex interaction of DNA repair factors and many steps remain poorly understood in mammals. The arrangement of homologous chromosomes is tightly regulated by the synaptonemal complex (SC). SYCP2 is an integral component of SCs in mammals. Our genetic and cell biological studies demonstrate that SYCP2 is required for the formation of SCs and chromosomal synapsis.

We also find that TEX11 interacts with SYCP2 and is a novel constituent of meiotic nodules involved in recombination. TEX11 promotes both synapsis and recombination, and thus may provide a physical link between these two fundamental meiotic processes.

We recently identified MEIOB, a meiosis-specific protein, in a proteomics screen for novel meiotic chromatin-associated proteins in mice. MEIOB contains an OB domain with homology to one of the RPA1 OB folds and thus is a meiosis paralogue of RPA1, a ubiquitously expressed single-strand DNA-binding protein. MEIOB binds to single-stranded DNA and exhibits 3'-5' exonuclease activity. MEIOB forms a complex with RPA and with SPATA22, another meiosis-specific protein in vertebrates. These three proteins co-localize in foci that are associated with meiotic chromosomes. Strikingly, chromatin localization and stability of MEIOB depends on SPATA22 and vice versa. Meiob-null mouse mutants exhibit a failure in meiosis and sterility in both sexes. Our data suggest that MEIOB may be required for the second end capture during meiotic recombination in mammals.

The G2/M Transition in Meiosis I

The meiotic prophase I to metaphase I (PI/MI; equivalent to the mitotic G2/M transition) transition requires chromosome desynapsis and metaphase competence acquisition. However, control of these major meiotic events is poorly understood. We identify an essential role for SKP1, a core subunit of the SKP1-Cullin-F-box (SCF) ubiquitin E3 ligase, in the PI/MI transition. SKP1 localizes to synapsed chromosome axes and evicts HORMAD proteins from these regions in meiotic spermatocytes. SKP1-deficient spermatocytes display premature desynapsis, precocious pachytene exit, loss of PLK1 and BUB1 at centromeres, but persistence of HORMAD, γH2AX, RPA2, and MLH1 in diplonema. Strikingly, SKP1-deficient spermatocytes show sharply reduced MPF activity and fail to enter MI despite treatment with okadaic acid. SKP1-deficient oocytes exhibit desynapsis, chromosome misalignment, and progressive postnatal loss. Therefore, SKP1 maintains synapsis in meiosis of both sexes. Furthermore, our results support a model where SKP1 functions as the long-sought intrinsic metaphase competence factor to orchestrate MI entry during male meiosis.

2021 - present

74. Chotiner JY, Leu NA, Yang F, Cossu IG, Guan Y, Lin H, and Wang PJ. TRIP13 localizes to synapsed chromosomes and functions as a dosage-sensitive regulator of meiosis. eLife. 2024.

73. Cossu IG, Leu NA, Guan Y, and Wang PJ. The N-terminal modification of HORMAD2 causes its ectopic persistence on synapsed chromosomes without meiotic blockade. Reproduction. 2024 Feb 1:REP-23-0330.

72. Wong H, Chen T, Wang PJ, Holzman L. ARF6, a component of intercellular bridges, is essential for spermatogenesis in mice. Dev. Biology. 2024 Jan 17:508:46-63.

71. Guan Y, Gao H, Leu NA, Vourekas A, Alexiou P, Maragkakis M, Mourelatos Z, Kang Z, Liang G, and Wang PJ. The MOV10 RNA helicase is a dosage-dependent host restriction factor for LINE1 retrotransposition in mice. PLoS Genetics. 2023;19(5):e1010566.

70. Lin L, Cossu IG, Leu NA, Deshpande AJ, Bernt KM, Luo M, & Wang PJ. The DOT1L-MLLT10 complex regulates male fertility and promotes histone removal during spermiogenesis. Development. 2023;150(9):dev201501.

69. Peart NJ, Johnson TA, Lee S, Sears MJ, Yang F, Quesnel-Vallières M, Feng H, Recinos Y, Barash Y, Zhang C, Hermann BP, Wang PJ, Geyer CB, Carstens RP. The germ cell-specific RNA binding protein RBM46 is essential for spermatogonial differentiation in mice. PLoS Genetics. 2022;18(9):e1010416. https://doi:10.1371/journal.pgen.1010416.

68. Lin H, Cheng K, Kubota H, Lan Y, Riedel SS, Kakiuchi K, Sasaki K, Bernt KM, Bartolomei MS, Luo M, Wang PJ. Histone methyltransferase DOT1L is essential for self-renewal of germline stem cells. Genes & Development. 2022;36(11-12):752-763. https://doi: 10.1101/gad.349550.122.

67. Ling L, Li F, Yang P, Oates RD, Silber S, Kurischko C, Luca FC, Leu NA, Zhang J, Yue Q, Skaletsky H, Brown LG, Rozen S, Page DC, Wang PJ, and Zheng K. Genetic characterization of a missense mutation in the X-linked TAF7L gene identified in an oligospermic man. Biology of Reproduction. 2022;107(1):157-167 . https://doi.org/10.1093/biolre/ioac093

66. Guan Y, Lin H, Leu NA, Ruthel G, Fuchs SY, Busino L, Luo M, and Wang PJ. SCF ubiquitin E3 ligase regulates meiotic DNA double-strand breaks in early meiotic recombination. Nucleic Acids Research, 2022 50(9):5129-5144. https://doi.org/10.1093/nar/gkac304

65. Yang F, Gervasi MG, Leu NA, Orta G, Tourzani DA, De la Vega-Beltrán JL, Ruthel G, Darszon A, Visconti PE, Wang PJ. C2CD6 regulates targeting and organization of the CatSper calcium channel complex in sperm flagella. Development. 2022;149(2):dev199988. https://doi.org/10.1242/dev.199988

64. Chotiner JY, Leu NA, Yang X, and Wang PJ. Recurrent pregnancy loss in mice lacking the X-linked Ccnb3 gene. Biology of Reproduction. 2022;106(3):382-384. https://doi.org/10.1093/biolre/ioab220.

63. Liu R, Kasowitz SD, Homolka D, Leu NA, Shaked JT, Ruthel G, Jain D, Keeny S, Luo M, Pillai RS, and Wang PJ. YTHDC2 is essential for pachytene progression and prevents aberrant microtubule-driven telomere clustering in male meiosis. Cell Reports. 2021;37(11):110110. https://doi.org/10.1016/j.celrep.2021.110110

62. Yin H, Kang Z, Zhang Y, Gong Y, Liu M, Xue Y, He W, Wang Y, Zhang S, Xu Q, Fu K, Zheng B, Jie Xie J, Zhang J, Wang Y, Lin M, Zhang Y, Feng H, Xin C, Guan Y, Huang C, Guo X, Wang PJ, Baur JA, Zheng K, Sun Z, Ye L. HDAC3 controls male fertility through enzyme-independent transcriptional regulation at the meiotic exit of spermatogenesis. Nucleic Acids Res. 2021;49(9):5106-5123.

61. Guan, Y and Wang, PJ. Golden opportunity for piRNA in female fertility. Nature Cell Biology. 2021; 23(9):936-938.  https://doi.org/10.1038/s41556-021-00749-z.

60. Guan Y, Keeney S, Jain D, and Wang PJ. yama, a mutant allele of Mov10l1, disrupts retrotransposon silencing and piRNA biogenesis. PLoS Genetics. 2021; 17(2):e1009265. https://doi.org/10.1101/2020.11.26.399659.

2016 - 2020

59. Chotiner JY, Leu NA, and Wang PJ. FLACC1 is testis-specific but dispensable for fertility in mice. Molecular Reproduction & Development. 2020 Dec;87(12):1199-1201 .

58. Guo R, Xu Y, Leu NA, Zhang L, Fuchs S, Ye L, and Wang PJ. The ssDNA-binding protein MEIOB acts as a dosage-sensitive regulator of meiotic recombination. Nucleic Acids Research. 2020 Dec 2;48(21):12219-12233.  

57. Li M, Feng H, Lin Z, Zheng J, Liu D, Guo R, Li J, Li RHW, Ng EHY, Huen MSY, Wang PJ, Yeung WSB, Liu K. The Novel Male Meiosis Recombination Regulator (MAMERR) Coordinates the Progression of Meiosis Prophase I. 2020; Journal of Genetics and Genomics, 2020 Aug;47(8):451-465.

56. Yang F, Lan Y, Pandey RR, Homolka D, Berger SL, Pillai RS, Bartolomei MS  and Wang PJ. TEX15 associates with MILI and silences transposable elements in male germ cells. Genes & Development. 2020;34(11-12):745-750. (journal cover).

https://doi: 10.1101/gad.335489.119.

55. Xu Y, Liu R, Leu NA, Zhang L, Ibragmova I, Schultz DC, and Wang PJ. A cell-based high-content screen identifies isocotoin as a small molecule inhibitor of the meiosis-specific MEIOB-SPATA22 complex. Biology of Reproduction. 2020; 103(2):333-342.

54. Zhang J, Gurusaran M, Fujiwara Y, Zhang K, Echbarthi M, Vorontsov E, Guo R, Pendlebury D, Alam I, Livera G, Martini E, Wang PJ, Nandakumar J, Davies O, Shibuya H. The BRCA2-MEILB2-BRME1 complex governs meiotic recombination and impairs the mitotic BRCA2-RAD51 function in cancer cells. Nature Communications. 2020;11(1):2055.

53. Guan Y, Leu NA, Ma J, Chamatal L, Ruthel G, Bloom JC, Lampson MA, Schimenti JC, Luo M, Wang PJ. SKP1 drives the prophase I to metaphase I transition during male meiosis. Science Advances. 2020; 6(13);eaaz2129. https://doi: 10.1126/sciadv.aaz2129.

52. Du G, Wang X, Luo M, Xu W, Zhou T, Wang M, Yu L, Li L, Cai L, Wang PJ, Li JZ, Oatley JM, Wu X. mRBPome capture identifies the RNA binding protein TRIM71, an essential regulator of spermatogonial differentiation. Development. 2020 Mar 18. pii: dev.184655. doi: 10.1242/dev.184655.

51. Lipschutz E, Dasgupta A, Guan Y, Kistler WS, Wang PJ. A rat H1t-GFP transgene recapitulates endogenous H1t expression pattern in mouse. Genesis. 2020 Jan 28:e23355. DOI:10.1002/dvg.23355.

50. Shi B, Xue J, Yin H, Guo R, Luo M, Ye L, Shi Q, Huang X, Liu M, Sha J, and Wang PJ. Dual functions for the ssDNA-binding protein RPA in meiotic recombination. PLoS Genetics. 2019, 15(2):e1007952. DOI: 10.1371/journal.pgen.1007952.

49. Kasowitz SD, Ma J, Anderson SJ, Leu NA, Xu Y, Gregory BD, Schultz RM, Wang PJ. Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development. PLoS Genetics. 2018, 14(5):e1007412.

DOI: 10.1371/journal.pgen.1007412.

48. Shi B, Xue J, Zhou J, Kasowitz SD, Zhang Y, Liang G, Guan Y, Shi Q, Liu M, Sha J, Huang X, Wang PJ. MORC2B is essential for meiotic progression and fertility. PLoS Genet. 2018, 14(1):e1007175. DOI: 10.1371/journal.pgen.1007175.

47. Kasowitz SD, Luo M, Ma J, Leu NA, and Wang PJ. Embryonic lethality and defective male germ cell development in mice lacking UTF1. Sci Rep. 2017, 7(1):17259.

46. Wang PJ. Tracking LINE1 retrotransposition in the germline. PNAS. 2017, 114(28):7194-7196.

45. Xu Y, Greenberg RA, Schonbrunn E, Wang PJ. Meiosis-specific proteins MEIOB and SPATA22 cooperatively associate with the single-stranded DNA-binding replication protein A complex and DNA double-strand breaks. Biol Reprod. 2017, 96(5), 1096–1104.

44. Fu Q, Pandey RR, Leu NA, Pillai RS, Wang PJ. Mutations in the MOV10L1 ATP hydrolysis motif cause piRNA biogenesis failure and male sterility in mice. Biol Reprod. 2016. 95 (5):103, 1-7.

43. Yang F and Wang PJ. Multiple LINEs of retrotransposon silencing mechanisms in the mammalian germline. Semin Cell Dev Biol. 2016;59:118-125.

2011 -2015

42. Zhou J, Stein P, Chmatal L, Leu NA, Xue J, Ma J, Huang X, Lampson M, Schultz RM, and Wang PJ. Accelerated reproductive aging in females lacking a novel centromere protein SYCP2L. Hum. Mol. Genet. 2015;24(22):6505-6514.

41. Yang F, Silber S, Leu NA, Oates RD, Marszalek JD, Skaletsky H, Brown LG, Rozen S, Page DC, Wang PJ. TEX11 is mutated in infertile men with azoospermia and regulates genome-wide recombination rates in mouse. EMBO Mol. Med. 2015 7(9):1198-1210.

40. Luo M, Zhou J, Leu NA, Abreu CM, Wang J, Anguera MC, de Rooij DG, Jasin M, Wang PJ. Polycomb Protein SCML2 Associates with USP7 and Counteracts Histone H2A Ubiquitination in the XY Chromatin during Male Meiosis. PloS Genetics, 2015 Jan 29;11(1):e1004954.

39. Yu Q, Carbone CJ, Katlinskaya YV, Zheng H, Zheng K, Luo M, Wang PJ, Greenberg RA, Fuchs SY. Type I interferon controls propagation of Long Interspersed Element-1. J. Biol. Chem. 2015 Feb 25. pii: jbc.M114.612374.

38. Vourekas A, Zheng K, Fu Q, Maragkakis M, Alexiou P, Ma J, Pillai RS, Mourelatos Z, and Wang PJ. MOV10L1 binds piRNA precursors to initiate piRNA processing. Genes & Development. 2015 29: 617-629.

Penn News: Penn Scientists Describe the Function of an Enzyme Critical to Male Fertility

37. Fu Q and Wang PJ. Mammalian piRNAs: biogenesis, function, and mysteries. Spermatogenesis. 2014;4:e27889. PMCID: PMC4114582

36. Zhou J, Leu NA, Goldberg EM, Coulter DA, Wang PJ. Respiratory failure, cleft palate, and epilepsy in the mouse model of human Xq22.1 deletion syndrome. Hum. Mol. Genetics. 2014;23(14):3823-3829. PMCID: PMC4065155 [Available on 2015/7/15]

Penn press release: Scientists from Penn and CHOP Confirm Link Between Missing DNA and Birth Defects.

35. Zhou J, Pan J, Eckardt S, Leu NA, McLaughlin KJ, Wang PJ. STK31/TDRD8, a germ cell-specific factor, is dispensable for reproduction in mice. PLoS One. 2014;9(2):e89471. PMCID: PMC3929691

34. Luo M, Yang F, Leu NA, Landaiche J, Handel MA, Benavente R, La Salle S, and Wang PJ. MEIOB exhibits single-stranded DNA-binding and exonuclease activities and is essential for meiotic recombination. Nature Communications. 2013;4:2788. PMCID: PMC3891831

33. Zhou H, Grubisic I, Zheng K, He Y, Wang PJ, Kaplan T, Tjian R. Taf7l cooperates with Trf2 to regulate spermiogenesis. Proc Natl Acad Sci U S A. 2013;110(42):16886-16891. PMCID: PMC3801064

32. Zhou J, McCarrey JR, Wang PJ. A 1.1 Mb segmental deletion on the X chromosome causes meiotic failure in male mice. Biol. Reprod. 2013;88(6):159.  PMCID: PMC4070866

31. Reynolds A, Qiao H, Yang Y, Chen JK, Jackson N, Biswas K, Holloway JK, Baudat F, de Massy B, Wang PJ, Höög C, Cohen PE, Hunter N. RNF212 is a dosage-sensitive regulator of crossing-over during mammalian meiosis. Nature Genetics. 2013;45(3):269-278.  PMID: 23396135

30. Zhou H, Kaplan T, Li Y, Grubisic I, Zhang Z, Wang PJ, Eisen MB, Tjian R. Dual Functions of TAF7L in Adipocyte Differentiation. eLife. 2013;2:e00170.  PMCID: PMC3539393

29. Zheng K and Wang PJ. Blockade of pachytene piRNA biogenesis reveals a novel requirement for maintaining post-meiotic germline genome integrity in mice. PLoS Genetics. 2012;8(11): e1003038.  PMCID: PMC3499362

Penn press release: A Class of RNA Molecules Protects Germ Cells From Damage, Penn Vet Researchers Show.

28. Berkowitz KM, Sowash AR, Koenig LR, Urcuyo D, Khan F, Yang F, Wang PJ, Jongens TA, and Kaestner KH. Disruption of Chtf18 causes defective meiotic recombination in male mice. PloS Genetics. 2012;8(11):e1002996. PMCID: PMC3486840

27. Yang F, Wei Q, Adelstein RS, Wang PJ. Non-muscle myosin IIB is essential for cytokinesis during male meiotic cell divisions. Dev Biol. 2012;369(2):356-61. PMCID: PMC3584343

26. Zhou J, Yang F, Leu NA, Wang PJ. MNS1 is essential for spermiogenesis and motile ciliary functions in mice. PLoS Genetics. 2012;8(3):e1002516.  PMCID: PMC3291534

Penn press release: Penn Vet Team Identifies a Gene Responsible for Male Infertility and a Respiratory Disorder.

25. Zhou J, Pan J, Eckardt S, Leu NA, McLaughlin KJ, Wang PJ. Nxf3 is expressed in Sertoli cells, but is dispensable for spermatogenesis. Mol Reprod Dev. 2011;78(4):241-9. PMCID: PMC3081378

2006 - 2010

24. Yang F, Cheng Y, An JY, Kwon YT, Eckardt S, Leu NA, McLaughlin KJ, Wang PJ. The ubiquitin ligase Ubr2, a recognition E3 component of the N-end rule pathway, stabilizes Tex19.1 during spermatogenesis. PLoS One. 2010; 5(11):e14017.  PMCID: PMC2982839

23. Shin YH, Choi Y, Erdin SU, Yatsenko SA, Kloc M, Yang F, Wang PJ, Meistrich ML, Rajkovic A. Hormad1 mutation disrupts synaptonemal complex formation, recombination, and chromosome segregation in mammalian meiosis. PLoS Genetics. 2010;6(11):e1001190. PMCID: PMC2973818

22. Zheng K, Xiol J, Reuter M, Eckardt S, Leu NA, McLaughlin KJ, Stark A, Sachidanandam R, Pillai RS, Wang PJ. Mouse MOV10L1 associates with Piwi proteins and is an essential component of the Piwi-interacting RNA (piRNA) pathway. Proc Natl Acad Sci U S A. 2010;107(26):11841-11846. PMCID: PMC2900664

21. Zheng K, Yang F, Wang PJ. Regulation of male fertility by X-linked genes. J Androl.  2010;31(1):79-85. PMCID: PMC2931805

20. Zheng K, Wu X, Kaestner KH, Wang PJ. The pluripotency factor LIN28 marks undifferentiated spermatogonia in mouse. BMC Dev Biol. 2009; 9(1):38. PMCID: PMC2719617

19. Pan J, Eckardt S, Leu NA, Buffone, M.G., Zhou J., Gerton G.L., McLaughlin KJ, Wang PJ. Inactivation of Nxf2 causes defects in male meiosis and age-dependent depletion of spermatogonia. Dev. Biol.  2009; 330:167-174. PMCID: PMC2702087

18. Yang F. and Wang P.J. The mammalian synaptonemal complex: a scaffold and beyond. Genome Dynamics. 2009(5):69-80. PMID: 18948708

17. Newell AE, Fiedler SE, Ruan JM, Pan J, Wang PJ, Deininger J, Corless CL, Carr DW. Protein kinase A RII-like (R2D2) proteins exhibit differential localization and AKAP interaction. Cell Motil. Cytoskeleton  2008; 65(7):539-52.  PMID:18421703

16. Yang F, Eckardt S, Leu NA, McLaughlin KJ, Wang PJ.  Mouse TEX15 is essential for DNA double-strand break repair and chromosomal synapsis during male meiosis.  J. Cell Biol.  2008; 180(4):673-679. PMCID: PMC2265566

15. Yang F, Gell K, van der Heijden GW, Eckardt S, Leu NA, Page DC, Benavente R, Her C, Höög C, McLaughlin KJ, Wang PJ.  Meiotic failure in male mice lacking an X-linked factor.  Genes & Development.  2008; 22(5):682-691. PMCID: PMC2259036

This article was featured in Penn Press Release on March 14, 2008: Penn Researchers Identify First Sex Chromosome Gene Involved in Meiosis and Male Infertility.

14. Honaramooz A, Megee S, Zeng W, Destrempes MM, Overton SA, Luo J, Galantino-Homer H, Modelski M, Chen F, Blash S, Melican DT, Gavin WG, Ayres S, Yang F, Wang PJ, Echelard Y, Dobrinski I. Adeno-associated virus (AAV) -mediated transduction of male germ line stem cells results in transgene transmission after germ cell transplantation. FASEB J. 2008;22(2):374-82. PMID: 17873102

13. Wang P.J. and Pan J.  The role of spermatogonially expressed germ cell-specific genes in mammalian meiosis. Chromosome Res. 2007;15(5):623-32. PMID: 17674150

12. Cheng Y., Buffone, M.G., Kouadio M., Goodheart M., Page D.C., Gerton G.L., Davidson I., and Wang P.J.  Abnormal sperm in mice lacking the Taf7l gene. Mol. Cell. Biol. 2007; 27(7):2582-2589. PMCID: PMC1899882

11. Yang F., Skaletsky H., and Wang P.J.  Ubl4b, an X-derived retrogene, is specifically expressed in post-meiotic germ cells in mammals. Gene Expr Patterns. 2007; 7(1-2):131-136. PMCID: PMC1647293

10. Yang F., De La Fuente R. Leu N.A., Baumann C, McLaughlin K.J., and Wang P.J. The mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis. J. Cell Biol. 2006;173(4):497-507. PMCID: PMC2063860

2001 - 2005

9. Pan J., Goodheart M., Chuma S., Nakatsuji N., Page D.C., and Wang P.J.  RNF17, a component of the mammalian germ cell nuage, is essential for spermiogenesis. Development 2005;132:4029-4039.  PMCID: PMC1994335

8. Wang P.J., Page D.C. and McCarrey J.R.  Differential expression of sex-linked and autosomal germ-cell-specific genes during spermatogenesis in the mouse. Hum. Mol. Genet. 2005;14:2911-2918. PMCID: PMC1994333

7. Wang P. J. (2004) X chromosomes, retrogenes and their role in male reproduction. Trends Endocrinol. Metab.  15(2):79-83. PMID: 15036254

6. Wang P.J. and Page D.C. (2002) Functional substitution for TAFII250 by a retroposed homologue that is expressed in human spermatogenesis.  Hum. Mol. Genet. 11(19):2341-2346. PMID: 12217962

5. Yang J., Bogerd H.P., Wang P.J., Page D.C. and Cullen B.R. (2001) Two closely related human nuclear export factors utilize entirely distinct export pathways. Mol. Cell  8:397-406. PMID: 11545741

4. Kosco K.A., Pearson C.G., Maddox P.S., Wang P.J., Adams I.R., Salmon E.D., Bloom K. and Huffaker T.C. (2001) Control of microtubule dynamics by Stu2p is essential for spindle orientation and metaphase chromosome alignment in yeast.  Mol. Biol. Cell  12(9):2870-2880. PMCID: PMC59720

3. Wang P.J., McCarrey J.R., Yang F. and Page D.C. (2001) An abundance of X-linked genes expressed in spermatogonia.  Nature Genetics.  27: 422-426. PMID:11279525

Before 2000

2. Wang P.J., Chabes A., Casagrande R., Tian X.C., Thelander L. and Huffaker T.C. (1997) Rnr4p, a novel ribonucleotide reductase small-subunit protein.  Mol. Cell. Biol.  17:6114-6121. PMCID: PMC232461

1. Wang P.J. and Huffaker T.C. (1997) Stu2p: A microtubule-binding protein that is an essential component of the yeast spindle pole body.  J. Cell Biol.  139:1271-1280. PMCID: PMC2140218

Alumni

• 2021 - 2023: Isabella Cossu, undergraduate and technician, Vet graduate student at PennVet.
• 2018 - 2022: Jessica Chotiner, CAMB graduate student, Senior Technical Account Manager at GenScript.
• 2019 - 2022: Huijuan Lin, joint-training graduate student, senior scientist at Chinese Academy of Sciences.
• 2015 - 2022: Yongjuan Guan, postdoc fellow, Professor at Capital Normal University.
• 2019 - 2021: Rong Liu, Visiting scholar, Associate Professor at Wuhan University.
• 2019 - 2021: Emma Lipschutz, Research Tech, Medical student at Drexel University.
• 2018 - 2020: Rui Guo, joint-training graduate student, Associate Professor at Anhui Medical University.
• 2018 - 2020: Jordan Shaked, Undergraduate, Medical student at Yale University.
• 2018 - 2019: Lei Zhang, postdoc fellow.
• 2012 - 2019: Seth Kasowitz, postdoc fellow, Senior Scientist at Addgene Inc.
• 2015 - 2018: Yang Xu, postdoc fellow, Scientist at Moderna.
• 2015 – 2018: Baolu Shi, visiting graduate student, currently postdoc at University of Sciences and Technology of China.
• 2014 – 2015: Jiangyang Xue, visiting graduate student, currently research scientist at Nanjing Medical University Affiliated Suzhou Hospital, China
• 2012 – 2016: Qi Fu, graduate student, postdoc in Robert Blelloch’s lab at UCSF
• 2010 – 2016: Mengcheng Luo, Postdoctoral fellow, currently Professor, Wuhan University, China
• 2008 - 2014: Jian Zhou, Ph.D., Postdoctoral fellow, currently Associate Professor, Shanghai Jiaotong University, China.
• 2007 - 2013: Ke Zheng, Ph.D., Postdoctoral fellow, Currently Professor, Nanjing Medical University, China.
• 2003 - 2008: Jieyan Pan, Research associate, Currently Research Specialist, University of Pennsylvania
• 2004 - 2005: Yong Cheng, Postdoctoral fellow, Currently Research Assistant Professor, Michigan State University

Wang Laboratory News and Updates

• 2023-10-26: Welcome Cong Liu to the lab.
• 2023-10-02: Welcome Yiyun Zhang to the lab.
• 2023-06-14: Isabella Cossu received the Bayard Storey research award at the CRRWH (Center for Research in Reproduction and Women's Health) research retreat.
• 2023-06-13: Zhenglong Kang received a oral presentation prize at BMS departmental retreat at Mutter Museum.
• 2022-11-02: Jessica Chotiner defended her thesis. Congratulations!
• 2022-06-06: Huijuan Lin's DOT1L manuscript on spermatogonial stem cells has been accepted at Genes & Development.
• 2022-05-13: Jeremy has been named Ralph L. Brinster President’s Distinguished Professor as the inaugural recipient.
• 2022-04-28: Fang Yang received a poster prize at the BMS Departmental retreat at Mutter Museum.
• 2022-04-28: Yongjuan Guan has accepted a faculty position at China Agricultural University.
• 2022-04-13: Yongjuan Guan's manuscript on the role of SKP1 in early meiotic recombination has been accepted in Nucleic Acids Research.
• 2021-12-01: Fang Yang's C2CD6 manuscript has been accepted for publication in Development.
• 2021-11-18: Jessica Chotiner's CCNB3 manuscript has been accepted for publication in Biology of Reproduction.
• 2021-11-17: Rong Liu's YTHDC2 manuscript has been accepted for publication in Cell Reports.

• 2020-02-09: Yongjuan Guan's MOV10L1 manuscript has been accepted for publication in PLoS Genetics.
• 2020-10-15: Jessica Chotiner's FLACC1 manuscript has been accepted for publication in Molecular Reproduction & Development.
• 2020-10-13: Rui Guo and Yang Xu's MEIOB human mutation manuscript has been accepted for publication in Nucleic Acids Research.
• 2020-06-09: Jordan Shaked, Penn graduating senior, received the Phi Beta Kappa Thesis Prize on the YTHDC2 research.
• 2020-06-05: Rui Guo successfully defended his thesis.
• 2020-04-20: Yang Xu and Rong Liu's manuscript on MEIOB/SPATA22 has been accepted for publication in Biology of Reproduction.
• 2020-04-03: Fang Yang's manuscript on TEX15 has been accepted for publication and selected for cover in Genes & Development.
• 2020-02-05: Jeremy received the SSR 2020 Research Award: https://www.ssr.org/awards-scholarships/awards2020
• 2020-01-17: Emma Lipschutz's paper on H1t-GFP has been accepted in Genesis.
• 2020-01-03: Yongjuan Guan's paper on the requirement of SKP1 in meiosis has been accepted in Science Advances.
• 2019-09-07: Welcome Rong Liu and Huijuan Lin to the lab.
• 2019-07-01: Jessica Chotiner received a spot in NIH T32 training grant in Developmental Biology.
• 2019-04-16: Jessica Chotiner's manuscript on "Functions of cyclins and CDKs in mammalian gametogenesis" has been accepted for publication in Biology of Reproduction.
• 2019-01-31: Congratulations to Seth Kasowitz on a senior scientist job offer from Addgene.
• 2019-01-24: Congratulations to Baolu Shi on the RPA1 paper in PLoS Genetics.
• 2018-10-01: Welcome,, Lei Zhang, research associate, to the lab!
• 2018-09-14: Welcome, Jordan Shaked, Penn Junior, to the lab!
• 2018-09-10: Welcome, Rui Guo, exchange graduate student, to the lab!
• 2018-06-19: Welcome, Jessica Chotiner, graduate student, to the Wang Laboratory!
• 2018-06-16: Baolu Shi received one of the best poster prizes at the Gordon conference - meiosis meeting at Colby-Saywer College (NH).
• 2018-05-22: Congratulations to Seth Kasowitz and Jun Ma on the YTHDC1 paper in PLoS Genetics.
• 2018-01-12: Congratulations to Baolu Shi and Jiangyang Xue on the MORC2B paper in PLoS Genetics.