Research Interests

Regulation of Spermatogenesis

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Dissecting genetic and epigenetic networks that control sperm production

Epigenetic Inheritance

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Germ cell-mediated transmission of epigenetic information 

Male Contraception

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Development of non-hormonal male birth control pills

Contributions to Science

Fundamentals of spermatogenesis

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 Discovered many cellular and molecular processes that control fundamental aspects of spermiogenesis, e.g., sperm connecting piece/neck formation, cytoplasmic removal, sperm transport from rete testis to epididymis, etc.   

Germ cell small RNA transcriptome

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 Defined the transcriptomes of various small RNA species in testis, ovary, spermatogenic cells and oocytes. Established the SpermBase, a database for sperm-borne small RNAs in various mammalian species.

Sperm small RNA-mediated epigenetic inheritance

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 Demonstrated that sperm-borne RNAs contribute to epigenetic inheritance and proposed novel ideas regarding the mechanisms of action of paternal/sperm or maternal/oocyte RNAs in epigenetic inheritance.  

 

Discovery of novel small RNA species

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 Reported endo-siRNAs in spermatogenic cells, in addition to ES cells and oocytes.  Discovered mitochondrial genome-encoded small RNAs (mitosRNAs).

 

Functions of germ cell small noncoding RNAs

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 Defined an essential role of miRNA and/or endo-siRNA biogenesis in gametogenesis and normal GI physiology.  Identified that two miRNA clusters, miR-449 and miR-34b/c, exclusively control multiciliogenesis.  

Non-hormonal male birth control pills

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We have identified spermdeformin 1 (SD-1) as an ideal drug candidate for reversible, non-hormonal male contraception.

Selected papers on regulation of spermatogenesis

  

  

  • Yan W, Assadi AH, Wynshaw-Boris A, Eichele G, Matzuk MM, Clark GD (2003) A novel role for platelet-activating factor acetylhydrolase 1b in mouse spermatogenesis. Proceedings of the National Academy of Sciences USA 100:7189-7194.
  • Yan W, Ma L, Burns KH, Matzuk MM (2003) Identification of a novel spermatid-specific linker histone H1 involved in chromatin remodeling during mammalian spermiogenesis. Proceedings of the National Academy of Sciences USA 100:10546-10551.
  • Greenbaum MP, Yan W*, Wu MH, Lin YN, Agno JE, Sharma M, Braun RE, Rajkovic A, Matzuk MM. (2006) TEX14 is essential for intercellular bridges and fertility in male mice. Proceedings of the National Academy of Sciences USA 103:4982-7. (*co-first authors)Yan W*, Ma L, Matzuk MM (2004) Haploinsufficiency of KLHL10 causes male infertility. Proceedings of the National Academy of Sciences USA 101:7793-7798. 
  • Zheng H, Stratton CJ, Morozumi K, Jin J, Yanagimachi R, Yan W* (2007) Lack of Spem1 causes aberrant cytoplasm removal, sperm deformation and male infertility. Proceedings of the National Academy of Sciences USA 104:6852-6857
  • Yuan S, Bao J, Stratton CJ, Bhetwal BP, Zheng H, Yan W* (2015) Spata6 is required for normal assembly of the sperm connecting piece and male fertility. Proceedings of the National Academy of Sciences USA. 112(5): E430-E439
  • Yuan S, Liu Y, Peng H, Tang C, Hennig GW, Wang Z, Yu T, Klukovich R, Zhang Y, Zheng H, Hess RA, Xu C, Wu J, Yan W* (2019) Motile cilia of the male reproductive system require miR-34/miR-449 for development and function to generate luminal turbulence. Proceedings of the National Academy of Sciences USA. 116(9):3584-3593

Selected papers on germ cell microRNAs and their functions

  

  • Ro S, Park C, Song R, Nguyen D, Jin J, Sanders KM, McCarrey JR, Yan W* (2007) Cloning and expression profiling of testis-expressed piRNA-like RNAs. RNA 13:1693-1702
  • Ro S, Park C, Young D, Sanders KM, Yan W*(2007) Tissue-dependent paired expression of miRNAs. Nucleic Acids Research 35:5944-5953
  • Ro S, Park C, Young D, Sanders KM, McCarrey JR, Yan W *(2007) Cloning and expression profiling of testis-expressed microRNAs Developmental Biology 311: 592-602
  • Ro S, Song R, Park C, Zheng H, Sanders KM, Yan W*(2007) Cloning and expression profiling of small RNAs expressed in the mouse ovary. RNA 13:2366-2380
  •  Song R, Michaels JD, Ro S, McCarrey JR, Yan W* (2009) X-linked microRNAs escape meiotic sex chromosome inactivation. Nature Genetics 41:488-493
  • Wu Q, Song R, Ortogero N, Zheng H, Evanoff R, Small CL, Griswold MD, Namekawa SH, Royo H, Turner JM, Yan W* (2012) The RNase III Enzyme DROSHA Is Essential for microRNA Production and Spermatogenesis. Journal of Biological Chemistry287(30): 25173-25190. 


Selected papers on sperm small RNA-mediated epigenetic inher

  

  • Yan W* (2014) Potential roles of noncoding RNAs in environmental epigenetic transgenerational inheritance. Molecular and Cellular Endocrinology10.1016/j.mce.2014.09.008
  • Yuan S, Oliver DK, Schuster A, Zheng H, Yan W*(2015) Breeding scheme and maternal small RNAs affect the efficiency of transgenerational inheritance of a paramutation in mice. Scientific Reports 5, Article number: 9266, doi:10.1038/srep09266
  • Chen Q*, Yan W*, Duan E* (2016) Inheritance of acquired traits thourgh sperm RNAs and sperm RNA modifications. Nature Reviews Genetics doi:10.1038/nrg.2016.106. (*Co-corresponding authors)
  • Skinner M, Maamar MB, Sadler-Riggleman I, Klukovich R, Beck D, Xie Y, Nillson E, McBirney, Tang C, Yan W(2018) Alteration in sperm DNA methylation, noncoding RNA and histone retention associate with DDT induced epigenetic transgenerational inheritance of disease. Epigenetics and Chromatin 11:8. https://doi.org/10.1186/s13072-018-0178-0.  
  • Schuster A, Skinner MK, Yan W (2016) Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs. Environmental Epigenetics 2(1): 1-10. DOI: http://dx.doi.org/10.1093/eep/dvw001 dvw001
  • Yuan S, Tang C, Schuster A, Zhang Y, Zheng H, Yan W (2016) Paternal pachytene piRNAs are not required for fertilization, embryonic development and sperm-mediated epigenetic inheritance in mice. Environmental Epigenetics DOI:10.1093/eep/dvw021.
  • Barouki R, Melen E, Herceg Z, Beckers J, Chen J, Karagas M, Puga A, Xia Y, Chadwick L, Yan W,Audouze K, Slama R, Heindel JJ, Grandjean P, Kawamoto T, Nohara K (2018) Epigenetics as a mechanism linking developmental exposures to long-term toxicity. Environmental International 144: 77-86. https://doi.org/10.1016/j.envint.2018.02.014
  • Skinner M, Maamar MB, Sadler-Riggleman I, Klukovich R, Beck D, Xie Y, Nillson E, McBirney, Tang C, Yan W (2018) Alteration in sperm DNA methylation, noncoding RNA and histone retention associate with DDT induced epigenetic transgenerational inheritance of disease. Epigenetics and Chromatin 11:8. DOI:10.1186/s13072-018-0178-0.
  • Ben Maamar M, Sadler-Riggleman I, Beck D, McBirney M, Nilsson E, Klukovich R, Xie Y, Tang C, Yan W*, Skinner M* (2018) Alterations in sperm DNA Methylation, noncoding RA expression, and histone retention mediate Vinclozolin induced epigenetic transgenerational inheritance of disease. Environmental Epigenetics 4, dvy010 (* co-corresponding author).
  • Nilsson E, Klukovich R, Sadler-Riggleman I, Beck D, Xie Y, Yan W*, Skinner MK* (2018) Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency. Epigenetics 13 (8): 875-895 DOI:10.1080/15592294.2018.1521223. PMC6224216
  • Klukovich R, Nilsson E, Sadler-Riggleman I, Beck D, Xie Y, Yan W*, Skinner MK* (2019) Environmental toxicant induced epigenetic transgenerational inheritance of prostate pathology and stromal-epithelial cell epigenome and transcriptome alterations: ancestral origins of prostate disease. Scientific Reports 18;9(1):2209. doi: 10.1038/s41598-019-38741-1
  • Wang Z, McSwiggin H, Newkirk SJ, Wang Y, Oliver D, Tang C, Lee S, Wang S, Yuan S, Zheng H, Ye P, An W, Yan W* (2019) Insertion of a chimeric retrotransposon sequence in mouse Axin1 locus causes metastable kinky tail phenotype. Mobile DNA 10:17 DOI: 10.1186/s13100-019-0162-7

Selected papers on discovery of novel small RNA species

  • Song R, Hennig G, Wu Q, Jose C, Zheng H, Yan W*(2011)Male germ cells express abundant endogenous siRNAs. Proceedings of the National Academy of Sciences USA. 108:13159-64.
  • Ro S, Ma HY, Park C, Ortogero N, Song R, Hennig GW, Zheng H, Lin YM, Moro L, Hsieh JT, Yan W* (2013) The Mitochondrial Genome Encodes Abundant Small Noncoding RNAs. Cell Research 23,759-774. Published online on12 March 2013, doi:10.1038/cr.2013.37 
  •   Ortogero N, Hennig GW, Luong D, Bao J, Bhetwal BP, Ro S, McCarrey JR, Yan W (2014) A Novel Class of Somatic Small RNAs Similar to Germ Cell Pachytene PIWI-interacting Small RNAs. Journal of Biological Chemistry 289 (47):32824-32834.
  • Ro S, Park C, Jin J, Sanders KM, Yan W(2006) A PCR-based method for detection and quantification of small RNAs. Biochemical and Biophysical Research Communications 351:756-763. 
  • Ro S, Yan W (2010) Detection and quantitative analysis of small RNAs by PCR. Methods in Molecular Biology 629:295-305.
  • Ro S, Yan W (2010) Small RNA cloning. Methods in Molecular Biology 629:273-85.
  • Song R, Ro S, Yan W (2010) In situ hybridization detection of microRNAs. Methods in Molecular Biology 629:287-94.
  • Ortogero N, Hennig GW, Langille C, Ro S, McCarrey JR, Yan W (2012) Computer-Assisted Annotation of the Sertoli Cell Small RNA Transcriptome. Biology of Reproduction 88 (1) 3:1-10. Published ahead of print November 7, 2012, doi:10.1095/biolreprod.112.102269 
  • Ortogero N, Hennig GW, Yan W (2014) Computer-assisted annotation of small RNA transcriptomes. Methods in Molecular Biology In Press, 2015;1218:353-64. doi:10.1007/978-1-4939-1538-5_22. PubMed PMID: 25319663.
  • Schuster A, Hennig GW, Ortogero N, Yan W (2014) In silico identification of novel endogenous small interference RNAs. Methods in Molecular Biology In Press, 2015;1218:341-51. doi:10.1007/978-1-4939-1538-5_21. PubMed PMID: 25319662.

     


Selected papers on functions of germ cell small RNAs

  

  • Park C, Yan W, Ward SM, Hwang SJ, Wu Q, Hatton W, Park J, Sanders KM, Ro S (2011) MicroRNAs dynamically remodel gastrointestinal smooth muscle cells. PLoS ONE 6(4): e18628. 
  • Park C, Hennig GW, Sanders KM, Cho JH, Hatton WJ, Redelman D, Park JK, Ward SM, Miano JM, Yan W, Ro S (2011) SRF-dependent microRNAs regulate gastrointestinal smooth muscle cell phenotypes, Gastroenterology 141(1): 164-175.
  • Bao J, Li D, Wang L, Wu J, Hu Y, Wang Z, Chen Y, Cao X, Jiang C, Yan W*, Xu C (2012) microRNA-449 and microRNA-34b/c function redundantly in murine testes by targeting the E2F transcription factor-Retinoblastoma protein (E2F-pRb) pathway. Journal of Biological Chemistry 287(26): 21686-21698. (*co-corresponding author)
  • Bao J, Zhang Y, Schuster A, Ortogero N, Nilsson EE, Skinner MK, Yan W(2014) Conditional inactivation of Miwi2reveals that MIWI2 is only essential for prospermatogonial development in mice. Cell Death and Differentiation 21: 783-796 (May 2014) | doi:10.1038/cdd.2014.5
  • Wu J, Bao J, Kim M, Yuan S, Tang C, Zheng H, Mastick GS, Xu C, Yan W (2014) Two miRNA clusters, miR-34b/c and miR-449, are essential for normal brain development, motile ciliogenesis and spermatogenesis. Proceedings of the National Academy of Sciences USA doi: 10.1073/pnas.1407777111; 111(28): E2851-E2857.
  • Yuan S, Ortogero N, Wu Q, Zheng H, Yan W (2014) Murine Follicular Development Requires Oocyte DICER, but Not DROSHA. Biology of Reproduction 114.119370
  • Yuan S, Schuster AS, Tang C, Ortogero N, Bao J. Zheng H, Yan W* (2016) Sperm-borne miRNAs and endo-siRNAs are important for fertilization and preimplantation development. Development 143(4): 635-647. doi: 10.1242/dev.131755