Despite the biological importance of mammalian meiosis, several of its significant features rema n largely unexplained. Recent discoveries by ourselves and others have shown that many of these features are controlled by the same protein, PRDM9. Our long-term objective is to determine how these controls are related, how they are achieved, and how PRDM9 fits into the larger network of proteins controlling meiosis progression. This will be greatly facilitated by the availability of multiple PRDM9 alleles in mice, each with its own regulatory specificities expressed in the most useful mammalian experimental model that we have. PRDM9 is an exceptional protein in the diversity of biological functions it carries out, in its unusual domain structure, and in its diverse molecular activities. The insights this study will provide extend beyond meiosis to major aspects of population genetics, as the location of hotspots determines patterns of inheritance;to genetic mapping studies identifying human disease genes;and to evolutionary biology, as allelic incompatibilities in PRDM9 can produce hybrid sterility. To address the relevant experimental questions, we have organized a coordinated effort among four projects representing diverse experimental approaches: genetics (Project A), protein chemistry (Project B), computational integration (Project 0), cell biology (Project D), and molecular biology (Projects A, B, C and D). Our Animal Resources Core will provide mice and new mutant strains. A Cell Biology Core will provide preparations of spermatocytes and assist in ChIP experiments. The Computational Core will perform data management and analysis. Our long-term objectives derive from the following overall program goals: a) Comprehensively define PRDM9's regulatory functions in recombination, transcription, and gametogenesis;b) Define the role of PRDM9 in regulation of meiosis by identifying and characterizing its interactions with genomic DNA, other meiotic proteins, and specialized meiotic structures;c) Define the overall role of PRDM9 in gametogenesis, hotspot activation, and transcription by using computational techniques to build an integrated model of its molecular functions;and d) Exploit the exceptional degree of variability in the Zn fingers (ZNF) of PRDM9 to clarify the complex nature of ZNF - DNA interactions, which are so ubiquitous in genomic regulation. Results of the program project will significantly increase the understanding of the mechanisms that regulate meiosis as well as their involvement in other important biological processes.

Public Health Relevance

Defects in meiosis, the specialized type of cell division through which sperm and eggs are produced, can result in infertility or subsequent embryonic loss. While the mechanisms that regulate meiosis are currently poorly understood, we and others recently discovered that a particular protein, PRDM9, plays a key role in regulating multiple meiotic processes. The proposed project to define the role of PRDM9 in regulation of meiosis will significantly increase our understanding of both normal meiosis and the factors that can go awry to impair human reproductive health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
1P01GM099640-01A1
Application #
8474281
Study Section
Special Emphasis Panel (ZRG1-GGG-F (40))
Program Officer
Janes, Daniel E
Project Start
2013-09-01
Project End
2018-07-31
Budget Start
2013-09-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$1,630,582
Indirect Cost
$698,821
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Baker, Christopher L; Walker, Michael; Kajita, Shimpei et al. (2014) PRDM9 binding organizes hotspot nucleosomes and limits Holliday junction migration. Genome Res 24:724-32