PTIP as an epigenetic regulator in male meiosis

Summary

Principal Investigator: Guo Zhang Zhu
Abstract: DESCRIPTION (provided by applicant): It is becoming evident that epigenetic mechanisms, including DNA methylation, histone modification and non-coding RNAs, play significant roles in spermatogenesis. Despite recent progress, our comprehension of the dynamic epigenome in developing male germ cells remains largely to be defined. Thus, it is time to identify novel epigenetic regulators and discover how they work in spermatogenesis. The goal of this application is to test the hypothesis that PTIP (PAX transcription activation domain interacting protein) is an essential epigenetic regulator in male meiosis. PTIP has been lately identified as part of a histone H3 lysine 4 (H3K4) methyltransferase complex and is essential for embryonic development. H3K4 methylation is an epigenetic mark and is involved in the regulation of genome function through modifying chromatin architecture. Given dynamic chromatin remodeling in spermatogenesis, we recently generated a transgenic mouse model with conditional knockout of PTIP in postnatal male germ cells. Remarkably, our preliminary data reveal that conditional knockout of PTIP in male germ cells leads to spermatogenesis arrest in meiosis prophase I, small testes, azoospermia, and sterility. Accordingly, two Specific Aims will be pursued in this application to test our hypothesis. Specific Aim 1: Further analyze meiotic phenotypes of PTIP- deficient male germ cells. We will accomplish this aim by implementing meiotic chromosome spread and immunofluorescence. Specific Aim 2: Determine PTIP-interacting proteins in spermatocytes. We will employ immunoaffinity chromatography followed by mass spectrometry to identify PTIP's functional partners. Successful completion of this project will considerably further our understanding of the germ cell epigenome during spermatogenesis and broadly define an epigenetic mechanism of cell differentiation and development. Furthermore, collected information may offer insights into unexplained (or idiopathic) infertility in men and may lead to new strategies for male contraception and assisted reproduction.
Funding Period: 2013-06-05 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. pmc PITX2 associates with PTIP-containing histone H3 lysine 4 methyltransferase complex
    Yan Liu
    Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, People s Republic of China
    Biochem Biophys Res Commun 444:634-7. 2014

Detail Information

Publications1

  1. pmc PITX2 associates with PTIP-containing histone H3 lysine 4 methyltransferase complex
    Yan Liu
    Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, People s Republic of China
    Biochem Biophys Res Commun 444:634-7. 2014
    ..Taken together, our data provide new mechanistic perspectives on PITX2's functions and its related biological processes. ..

Research Grants30

  1. Investigating the role of dUTX in Drosophila male germ cell differentiation
    Lama Tarayrah; Fiscal Year: 2013
    ..Results from this study will have significant implications on cancer biology and regenerative medicine. ..
  2. Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells
    Rama Natarajan; Fiscal Year: 2013
    ..The results can increase our understanding of Ang II actions, and identify new targets that might be developed as clinical therapies for CVDs such as hypertension and atherosclerosis. ..
  3. Spatio-temporal dynamics of GEF-GTPase networks
    KLAUS MICHAEL HAHN; Fiscal Year: 2013
    ..abstract_text> ..
  4. Epigenetic regulation of transcription by mixed lineage leukemia protein MLL1
    Yali Dou; Fiscal Year: 2013
    ..This project is to understand the fundamental mechanism for these changes and thus, the cause of the disease. It will set up the foundation for potential medical interference in the future. ..
  5. Functional Analysis of the Embryonic Epigenome in a Non-rodent Model
    Mark E Westhusin; Fiscal Year: 2013
    ....
  6. Epigenetic Control of a Ras Activator
    Paul D Soloway; Fiscal Year: 2013
    ..Such studies are fundamental to understand how epigenetic states are controlled and will identify critical points of regulation where this control can go awry in human disease. ..
  7. Repression via Facultative Heterochomatin.
    DANNY F REINBERG; Fiscal Year: 2013
    ..The aim of this proposal is to better understand the molecular mechanisms involved in this process, and their role in disease such as cancer. ..
  8. The MRAD9 Radioresistance Gene
    Howard B Lieberman; Fiscal Year: 2013
    ..abstract_text> ..
  9. Center for the Study of Reproductive Biology and Women's Health
    Jeffrey W Pollard; Fiscal Year: 2013
    ..He holds several senior administrative appointments in the College of Medicine and is well able to administer the proposed SCCPIR internally and to enable effective interactions with other SCCPIRs. ..