Although inheritance of DNA sequence underpins the majority of heritability in biology, it is increasingly clear that information beyond the genome ? known as epigenetic information ? is also transmitted to the next generation, with vast implications for health and development. Over the past decade, we have developed several paternal-effect paradigms in mice to address how epigenetic information in gametes affects the phenotype of offspring, and whether an animal's environmental conditions can affect heritable epigenetic information, thereby ?reprogramming? the offspring's phenotype. We discovered that paternal environmental exposures can reproducibly alter offspring physiology, and we are uncovering molecular mechanisms underlying this information transfer, focusing on the largely unexplored role for sperm RNAs in control of early mammalian development. Small RNAs play central roles in well-characterized transgenerational epigenetic inheritance paradigms such as paramutation in maize and RNA interference in C. elegans, and it is increasingly clear that small RNAs in mammalian sperm play key functional roles in the early embryo. Not only is the overall sperm small RNA payload essential for early development, but the levels of many specific small RNAs in sperm have been shown to change in response to paternal environmental conditions. These early and exciting studies motivate a more thorough characterization of the role of small RNAs in mammalian development. Here, we propose to take a three part approach to the regulation and function of sperm small RNAs in preimplantation embryos. In the first part, we propose to systematically characterize the functions of sperm RNAs in the early embryo, manipulating small RNA levels in zygotes and measuring resulting regulatory consequences by single-embryo RNA-Seq. Next, we plan to survey the landscape of environmental effects on sperm RNAs, establishing most of the credible paternal effect paradigms under the same conditions and measuring sperm RNA levels and resulting early embryonic regulatory consequences in response to these environmental perturbations. Finally, we seek to uncover the mechanisms underlying the functions of 5' tRNA fragments, an understudied class of regulatory molecules which comprise the dominant small RNA species carried by mature mammalian sperm. Together, these studies will provide unprecedented insights into the regulation of small RNA levels in mammalian sperm, and their functions in the preimplantation embryo. These systematic analyses of epigenetic signals in sperm will not only reveal new principles of biological inheritance, but will also enable us to predict and potentially manipulate offspring phenotypes in ways that promote health.
Relevancy Statement/Project Narrative Epigenetic inheritance, the inheritance of information beyond DNA sequence, has been proposed to carry information about the environment between generations. We have discovered in mice that paternal environmental conditions, such as diet or nicotine exposure, can have a profound influence on offspring's metabolic state. In this grant we propose to thoroughly investigate the mechanisms underlying transgenerational control of metabolic state in mammals, with important implications for the epidemiology of common human diseases such as diabetes.
|Conine, Colin C; Sun, Fengyun; Song, Lina et al. (2018) Small RNAs Gained during Epididymal Transit of Sperm Are Essential for Embryonic Development in Mice. Dev Cell 46:470-480.e3|
|Chan, Io Long; Rando, Oliver J; Conine, Colin C (2018) Effects of Larval Density on Gene Regulation in Caenorhabditis elegans During Routine L1 Synchronization. G3 (Bethesda) 8:1787-1793|
|Sharma, Upasna; Sun, Fengyun; Conine, Colin C et al. (2018) Small RNAs Are Trafficked from the Epididymis to Developing Mammalian Sperm. Dev Cell 46:481-494.e6|
|Vallaster, Markus P; Kukreja, Shweta; Bing, Xin Y et al. (2017) Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring. Elife 6:|
|Sharma, Upasna; Rando, Oliver J (2017) Metabolic Inputs into the Epigenome. Cell Metab 25:544-558|
|Wang, Feng; McCannell, Kurtis N; Boškovi?, Ana et al. (2017) Rlim-Dependent and -Independent Pathways for X Chromosome Inactivation in Female ESCs. Cell Rep 21:3691-3699|
|Chou, Hsin-Jung; Donnard, Elisa; Gustafsson, H Tobias et al. (2017) Transcriptome-wide Analysis of Roles for tRNA Modifications in Translational Regulation. Mol Cell 68:978-992.e4|
|Wang, Feng; Shin, JongDae; Shea, Jeremy M et al. (2016) Regulation of X-linked gene expression during early mouse development by Rlim. Elife 5:|
|Hainer, Sarah J; McCannell, Kurtis N; Yu, Jun et al. (2016) DNA methylation directs genomic localization of Mbd2 and Mbd3 in embryonic stem cells. Elife 5:|
|Sharma, Upasna; Conine, Colin C; Shea, Jeremy M et al. (2016) Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351:391-396|
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