Dr. Jeremy Wang is professor of developmental biology in the Department of Biomedical Sciences and director of the Center for Animal Transgenesis and Germ Cell Research. Dr. Wang received his MD from Peking University Health Sciences Center in 1990. After receiving his Ph.D. in biochemistry, cell and molecular biology from Cornell University in 1997, he worked as a post-doctoral fellow in the Laboratory of Dr. David Page at the Whitehead Institute/Massachusetts Institute of Technology (M.I.T.) before joining Penn Vet as an assistant professor in 2002. Dr. Wang’s research interests are centered on the genetic regulation of germ cells in mice and humans, focusing on meiosis, transposon silencing, maternal factors, sperm motility, male infertility, and male contraception. In the past 16 years, Dr. Wang has sought to understand the regulation of spermatogenesis by assessing the function of dozens of novel germ cellspecific proteins that he and his lab identified using two innovative costeffective genome-wide screens. In the first screen, which Dr. Wang carried out as a postdoc at the Whitehead Institute, he developed a cDNA subtraction approach (in the pre-microarray era) and identified 36 germ cellspecific genes, 24 of which were novel (1). Since then, his laboratory has published genetic studies on more than 10 of these genes. In the second genome-wide screen, Wang and coworkers undertook a proteomics approach and identified 51 meiotic chromatin-associated proteins in mouse, 32 of which were uncharacterized (2). To date, the Wang laboratory has published functional studies of four proteins (MEIOB, SCML2, UTF1, and YTHDC1) identified in the proteomics screen. These two genome-wide screens represent significant contributions to the field of mammalian reproduction, since study of these genes has provided unique molecular insights into spermatogenesis in mice. Moreover, the results of these studies have important implications for understanding the genetic causes of male infertility in humans and identifying novel targets for male contraception.
Meiosis and Fertility
Meiosis, a cell division unique to germ cells, allows the reciprocal exchange of genetic materials between paternal and maternal genomes through meiotic recombination. Thus, meiosis generates the genetic diversity necessary for species evolution. Importantly, abnormalities in meiosis and aberrant recombination are a leading cause of birth defects and infertility. During meiosis, homologous chromosomes undergo synapsis and recombination. Meiotic recombination begins with generation of programmed DNA double-strand breaks (~300 DSBs per germ cell). This process relies on the complex interplay of DNA repair proteins.
However, as meiotic recombination occurs between non-sister chromatids (homologues) rather than sister chromatids as in somatic cells, many DNA repair proteins have evolved to function specifically during meiosis. The Wang laboratory has identified and studied a number of such meiosis-specific factors, including SYCP2, TEX11, and MEIOB (Figure 1) and have found that SYCP2 is an integral component of the synaptonemal complex (SC), which physically connects the homologous chromosomes (Fig. 1). They also find that TEX11 interacts with SYCP2 and is a novel factor involved in recombination (Fig. 1A). TEX11 promotes both synapsis and recombination (3). Notably, inactivation of Tex11, an X-linked gene, causes meiotic defects and sterility in males (Fig. 1B). By screening hundreds of infertile men, the Wang laboratory have shown that mutations in the TEX11 gene alone account for 1% of cases of azoospermia (infertile men with no sperm in semen) (4). Thus, our study on Tex11 in mice provides a strong rationale for screening for TEX11 mutations in infertile men to further inform genetic consultations with couples seeking infertility treatment. Dr. Wang’s group also identified MEIOB, a meiosis-specific protein, in the aforementioned proteomics screen (2). MEIOB binds to ssDNA and localizes to DSBs in meiotic germ cells (Fig. 1C). Meiob-null mice exhibit a failure in meiosis and sterility in both sexes (Fig. 1D). MEIOB forms a heterodimer with SPATA22, another meiosis-specific protein. Disruption of the interaction between MEIOB and SPATA22 destabilizes both proteins (5), raising the intriguing possibility that small molecule inhibitors of the MEIOB-SPATA22 interaction could be further developed for male contraception.
Transposon Silencing and Genome Evolution
Repetitive elements, term “junk DNA”, occupy ~40% of the mammalian genome and include retrotransposons such as LINEs, SINEs, and endogenous retroviruses. Retrotransposons have an enormous capacity to metastasize throughout the genome using a “copy and paste” mechanism involving reverse transcription. While retrotransposons play an important role in genome evolution, their mobilization can be detrimental to genome integrity, particularly in germ cells. In most species, the inability to silence retrotransposons in the germline is often associated with sterility. To protect genome integrity, germ cells employ multiple mechanisms to suppress retrotransposon activity, including small non-coding piRNAs, DNA methylation, and repressive histone modifications. Piwi-interacting RNAs (piRNAs) are a diverse class of small noncoding RNAs required for the silencing of retrotransposons and the safeguarding of genome integrity. In mammals, piRNAs are only present in male germ cells. In collaboration with Dr. Zissimos Mourelatos’ laboratory at Perelman School of Medicine, Dr. Wang and colleagues find that MOV10L1, a putative RNA helicase identified in the genomic screen described above (1), binds to piRNA precursors to initiate piRNA biogenesis. This result identified MOV10L1 as a master regulator of the piRNA pathway in mammals (6). Loss of Mov10l1 results in absence of piRNAs, activation of retrotransposons, and male sterility. In the future, the Wang laboratory will continue to investigate the genetic and epigenetic mechanisms of retrotransposon silencing in germ cells.
Dr. Wang’s research is funded by the NIH/NIGMS MIRA award (R35GM118052) and NIH/ NICHD grants (R01HD069592, R01HD084007, and P50 Center Grant HD068157). His laboratory is located at 304 Rosenthal and his office is at 390EC Rosenthal/Old Vet.
- Wang PJ, McCarrey JR, Yang F, Page DC. (2001) An abundance of X-linked genes expressed in spermatogonia. Nat Genet 27:422-426.
- Mengcheng Luo, Fang Yang, N. Adrian Leu, Jessica Landaiche, Mary Ann Handel, Ricardo Benavente, Sophie La Salle & P. Jeremy Wang (2013) MEIOB exhibits single-stranded DNA-binding and exonuclease activities and is essential for meiotic recombination. Nat Commun 4:2788.
- Yang F, Gell, K van der Heijden GW, Eckardt S, Leu NA, Page DC, Benavente R Her C, Hoog, C, McLaughlin KJ, and Wang PJ. (2008) Meiotic failure in male mice lacking an X-linked factor. Genes Dev 22:682-691.
- Yang F, Silber S, Leu NA, Oates RD, Marszalek JD, Skaletsky H, Brown LG, Rozen S, Page DC, Wang PJ. (2015) TEX11 is mutated in infertile men with azoospermia and regulates genome-wide recombination rates in mouse. EMBO Mol Med 7:1198-1210.
- Xu Y, Greenberg RA, Schonbrunn E, Wang PJ. (2017) Meiosis-specific proteins MEIOB and SPATA22 cooperatively associate with the ssDNA-binding RPA complex and DNA double-strand breaks. Biol Reprod 96:1096-1104.
- Vourekas A, Zheng K, Fu Q, Maragkakis M, Alexiou P, Ma J, Pillai RS, Mourelatos Z, Wang PJ (2015) The RNA helicase MOV10L1 binds piRNA precursors to initiate piRNA processing. Genes Dev 29(6):617-629.
The Wang research group—Emma Lipschutz, Jessica Chotiner, Fang Yang, Yongjuan Guan, Baolu Shi, Jeremy Wang, & Seth Kasowitz—notice the unique tiedye lab coats in the Wang Laboratory