The epigenome consists of several types of chemical modifications on either histone proteins or DNA. In somatic cells, these modifications are maintained across mitotic divisions, whereas in the germline and embryo, the epigenome is reset to ensure proper development and to prevent the trans-generational inheritance of acquired epigenetic information. Despite the two waves of genome-wide reprogramming during mammalian development, the inheritance of epigenetic information has been observed in various organisms, including humans. These findings raise a fundamental question: is epigenetic information in gametes transmitted from generation to generation and, if so, what are the consequences of trans-generational epigenetic inheritance? The epigenetic contribution from the paternal genome is considered limited since the sperm genome is largely depleted of histones. The small amounts of histones retained in sperm were believed to be remnants of incomplete histone-to-protamine exchange. However, my studies revealed that key developmental gene promoters in sperm are DNA hypomethylated and are enriched for both active and repressive histone modifications: a ?poised? chromatin state presumed to be specific to a totipotent/pluripotent cell. However, our findings demonstrated that competency for totipotency is already embedded in sperm chromatin, and possibly inherited through the paternal lineage, therefore, challenging prior notions and expanding the breadth of paternal contribution to the developing embryo beyond the DNA sequence. Furthermore, subsequent studies have shown that the epigenetic modifications retained in sperm chromatin are distinct from those present in the oocyte. Whether these retained parent-of-origin epigenetic marks (apart from imprinted genes) are instructive for early embryonic development or the first cell fate determination events remains unknown. This proposal aims to address two fundamental questions in biology: 1) What is the biological function and significance of retained histones and their attendant modifications in sperm, and 2) Is the preservation of the parent-of-origin epigenetic marks (apart from imprinted genes) important for early development and the first cell fate determination events or are these marks merely a remnant of the paternal or maternal origin of the genomes? To address these questions and others, we propose to develop exciting, cutting edge cell biology and molecular genetic tools that will enable the visualization, tracking, and temporal control of paternal histones in the developing embryo. Through these studies we hope to uncover whether the modified nucleosomes retained in sperm chromatin are inherited and instructive for development, therefore, providing a molecular mechanism for transgenerational inheritance, a notion supported by observation, yet without a clear molecular explanation.

Public Health Relevance

This proposal aims to delineate the role and significance of epigenetic information embedded in sperm chromatin on future generations. Recent data has suggested that the zygote retains some epigenetic memory from gametes, which implies that epigenetic changes accrued over an organism's lifetime may affect developmental competence or leave heritable marks on future generations. Therefore, defining and understanding the molecular carriers of epigenetic information transgenerationally has great implications for human health and reproductive success.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2HD091949-01
Application #
9165573
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (56)R)
Program Officer
Moss, Stuart B
Project Start
2016-09-06
Project End
2021-06-30
Budget Start
2016-09-06
Budget End
2021-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$2,325,000
Indirect Cost
$825,000
Name
University of Michigan Ann Arbor
Department
Genetics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109