Contributions to Science:

1. 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. Using the gene knockout approach, we have defined the physiological roles of >20 genes that are either exclusively or preferentially expressed in developing male or female germ cells. These genes include Gasz, Zfp393, Pafa1b, Tex14, Hisl1, Tektin3, Klhl10, Oasl6, Catsper3, Catsper4, Spem1, Fank1, Stk31, Spata6, Ubqln3, Ubqlnl, Upf2, etc. Five representative papers are as follows:

  • Yan W*, Ma L, Matzuk MM (2004) Haploinsufficiency of KLHL10 causes male infertility. Proceedings of the National Academy of Sciences USA 101:7793-7798. (*Coresponding author)
  • 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 USA104:6852-6857 (*Coresponding author)
  • 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 (*Coresponding author)
  • Bao J*, Vitting-Seerup K, Waage J, Tang C, Ge Y, Porse BT*, Yan W* (2016) UPF2-mediated nonsense mRNA decay participates in 3'UTR shortening during male germ cell development. PLoS Genetics12(5): e1005863. DOI: 10.1371/journal.pgen.1005863. (*Coresponding author)

2. Defined miRNA transcriptomes in testis, ovary, spermatogenic cells and oocytes. 
 The Yan lab was among the first that systematically determined the expression profiles of miRNAs in testis, ovary, spermatogenic cell and oocytes, as evidenced by the following four papers in 2007:

  • 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. RNA13:1693-1702 (*Coresponding author)
  • Ro S, Park C, Young D, Sanders KM, Yan W* (2007) Tissue-dependent paired expression of miRNAs. Nucleic Acids Research35:5944-5953. (*Coresponding author)
  • Ro S, Park C, Young D, Sanders KM, McCarrey JR, Yan W *(2007) Cloning and expression profiling of testis-expressed microRNAs. Developmental Biology311: 592-602. (*Coresponding author)
  • 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. (*Coresponding author)

3. First discovered X-linked miRNAs escaping MSCI, endo-siRNAs in the male germline, and mitochondrial genome-encoded small RNAs, called mitosRNAs.  
The Yan lab first reported that X-linked miRNAs, most of which are exclusively or preferentially expressed in spermatogenic cells, escape the meiotic sex chromosome inactivation (MSCI).  We first reported that endo-siRNAs are abundantly expressed and function in spermatogenic cells, in addition to ES cells and oocytes.  We were also the first who discovered and studied the function of mitosRNAs. 

  • Song R, Michaels JD, Ro S, McCarrey JR, Yan W* (2009) X-linked microRNAs escape meiotic sex chromosome inactivation.Nature Genetics 41:488-493. (*Coresponding author)
  • 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. (*Coresponding author)
  • 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 Chemistry 287(30): 25173-25190. (*Coresponding author)
  • 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 on 12 March 2013, doi:10.1038/cr.2013.37 (*Coresponding author)

4. Defined the physiological roles of bulk and individual miRNAs, endo-siRNAs, and piRNAs in reproduction. 
By inactivating Dicer and Drosha in the germline and the GI smooth muscle cells, we have defined the essential roles of miRNAs and/or endo-siRNAs in gametogenesis and normal GI physiology. Comprehensive molecular characterization in conjunction with gene knockout technologies have led us to identify physiological roles of two miRNA clusters, miR-449 and miR-34b/c in motile ciliogenesis, spermatogenesis and brain development. The following representative papers demonstrate this contribution:

  • 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. (*Coresponding author)
  • Bao J, Zhang Y, Schuster A, Ortogero N, Nilsson EE, Skinner MK, Yan W* (2014) Conditional inactivation of Miwi2 reveals 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 (*Coresponding author)
  • 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 USAdoi: 10.1073/pnas.1407777111; 111(28): E2851-E2857. (*Coresponding author)
  • 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 (*Coresponding author)

5. 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. 
We first demosntarted that intercrossing causes long-lasting transgenerational epigenetic inheritance, and that paternal and maternal noncoding RNAs play a critical role in post-fertilization development and transmitting the epigenetic memory to offspring. 

  • 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. (*Coresponding author)
  • Yan W* (2014) Potential roles of noncoding RNAs in environmental epigenetic transgenerational inheritance. Molecular and Cellular Endocrinology10.1016/j.mce.2014.09.008. (*Coresponding author)
  • Schuster A, Skinner MK*, Yan W* (2016) Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs. Environmental Epigenetics2(1): 1-10. DOI: dvw001. (*Coresponding author)
  • Chen Q*, Yan W*, Duan E*. (2016) Inheritance of acquired traits via sperm RNAs and RNA modifications. Nature Reviews Genetics doi:10.1038/nrg.2016.106. (*Coresponding author)

6. Established novel methodologies for small noncoding RNA analyses. 
We have developed miRNA detection and quantitation methods, small noncoding RNA (sncRNA) sequencing methods and sncRNA-Seq annotation pipelines. The following seven method papers document the achievements:

  • 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. (*Coresponding author)
  • 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 Biology629:273-85. (*Coresponding author)
  • Song R, Ro S, Yan W* (2010) In situ hybridization detection of microRNAs. Methods in Molecular Biology629:287-94. (*Coresponding author)
  • 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. (*Coresponding author)
  • Ortogero N, Hennig GW, Yan W* (2014) Computer-assisted annotation of small RNA transcriptomes.  Methods in Molecular Biology 2015;1218:353-64. doi:10.1007/978-1-4939-1538-5_22. PubMed PMID: 25319663. (*Coresponding author)
  • Schuster A, Hennig GW, Ortogero N, Yan W* (2014) In silico identification of novel endogenous small interference RNAs. Methods in Molecular Biology 2015;1218:341-51. doi:10.1007/978-1-4939-1538-5_21. PubMed PMID: 25319662. (*Coresponding author)

University of Nevada, Reno School of Medicine

University of Nevada, Reno School of Medicine

We study genetic and epigenetic regulation of gametogenesis, as well as epigenetic contribution of gametes (i.e., sperm and eggs) to fertilization and preimplantation development.

Current research projects:

  • Genetic networks regulating spermiogenesis, the process through which round spermatids differentiate into spermatozoa.
  • Roles of noncoding RNAs in the regulation of gametogenesis, fertilization and early embryonic development.
  • Noncoding RNAs-mediated epigenetic transgenerational inheritance.
  • Development of non-hormonal male contraceptives.