Dr Ian Adams: Chromosomes and Gene Expression

Chromosomes in meiosis. Chromosome axes are labelled red, and centromeres labelled green.

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Genetic and Chromosomal Stability in Mammalian Germ Cells

 

Summary

Germ cells are responsible for transmitting genetic information from one generation to the next. Meiosis, a specialised form of cell division that halves the number of chromosomes in male and female germ cells, is central to germ cell development and heredity. We are interested in how male and female germ cells protect the genome from mutation during their development, and how the germ cells ensure that the correct number of chromosomes is transmitted from generation to generation.

 

 

 

Key Publications

  1. Reichmann J, Reddington JP, Best D, Read D, Ollinger R, Meehan RR, and Adams IR. 2013. The genome-defence gene Tex19.1 suppresses LINE-1 retrotransposons in the placenta and prevents intra-uterine growth retardation in mice. Hum. Mol. Genet. 22:1791-1806, 2013.
  2. Hackett JA, Reddington JP, Nestor CE, Dunican DS, Branco, MR, Reichmann J, Reik W, Surani, MA, Adams, IR & Meehan, RR: Promoter DNA methylation couples genome-defence mechanisms to epigenetic reprogramming in the mouse germline. Development. 139:3623-3632, 2013.
  3. Reichmann J, Crichton JH, Madej MJ, Taggart M, Gautier P, Garcia-Perez JL, Meehan RR, Adams IR: Microarray analysis of LTR retrotransposon silencing identifies Hdac1 as a regulator of retrotransposon expression in mouse embryonic stem cells. PLoS Comput. Biol. 8:e1002486, 2012.
  4. Ollinger, R.; Childs, A.J.; Burgess, H.M.; Speed, R.M.; Lundegaard, P.R.; Reynolds, N.; Gray, N.K.; Cooke, H.J. and Adams, I.R. Deletion of the pluripotency-associated Tex19.1 gene causes activation of endogenous retroviruses and defective spermatogenesis in mice. 
    PLoS Genet. 4(9):e1000199, 2008.

 

Recent Publications

  1. Crichton JH, Dunican DS, Maclennan M., Meehan RR & Adams IR: Defending the genome from the enemy within: mechanisms of retrotransposon suppression in the mouse germline. Cell. Mol. Life Sci., 2013
  2. Adams, IR & Meehan, RR: From paramutation to paradigm. PLoS Genet. 9:e1003537, 2013.
  3. Chapman, JR, Barral, P, Vannier, J-B, Borel, V, Steger, M, Tomas-Loba, A, Sartori, AA, Adams, IR, Batista, FD & Boulton, SJ: RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol. Cell 49:858-871, 2013.
  4. Reddington JP, Perricone SM, Nestor CE, Reichmann J, Youngson NA, Suzuki M, Reinhardt D, Dunican DS, Prendergast JG, Mjoseng H, Ramsahoye BH, Whitelaw E, Greally JM, Adams IR, Bickmore WA & Meehan RR: Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes. Genome Biol. 14:R25, 2013.
  5. Reichmann J, Reddington JP, Best D, Read D, Ollinger R, Meehan RR, and Adams IR:The genome-defence gene Tex19.1 suppresses LINE-1 retrotransposons in the placenta and prevents intra-uterine growth retardation in mice. Hum. Mol. Genet. 22:1791-1806, 2013.
  6. Reichmann J, Crichton JH, Madej MJ, Taggart M, Gautier P, Garcia-Perez JL, Meehan RR, Adams IR: Microarray analysis of LTR retrotransposon silencing identifies Hdac1 as a regulator of retrotransposon expression in mouse embryonic stem cells. PLoS Comput. Biol. 8:e1002486, 2012.
  7. Chassot AA, Gregoire EP, Lavery R, Taketo MM, de Rooij DG, Adams IR, Chaboissier MC: RSPO1/beta-catenin signaling pathway regulates oogonia differentiation and entry into meiosis in the mouse fetal ovary
    PLoS One 6:e25641, 2011.
  8. Madsen L, Kriegenburg F, Vala A, Best D, Prag S, Hofmann K, Seeger M, Adams IR, Hartmann-Petersen R: The tissue-specific Rep8/UBXD6 tethers p97 to the endoplasmic reticulum membrane for degradation of misfolded proteins. PLoS One 6:e25061, 2011.
  9. Ollinger R, Reichmann J, Adams, IR: Meiosis and retrotransposon silencing during germ cell development in mice. Differentiation 79:147-158, 2010.
  10. Adams IR: Cycling mouse oocytes through meiosis. Cell Cycle 9:643-644, 2010.
  11. Best, D and Adams, IR: Sdmg1 is a component of secretory granules in mouse secretory exocrine tissues. Dev. Dyn. 238:223-231, 2009.
  12. Kocer A, Reichmann J, Best D, and Adams IR: Germ Cell Sex Determination in Mammals. Mol. Hum. Reprod. 15:205-213, 2009.
  13. Best D, Sahlender DA, Walther N, Peden AA, Adams IR: Sdmg1 is a conserved transmembrane protein associated with germ cell sex determination and germline-soma interactions in mice. Development. 135:1415-1425, 2008

 

Lab Members

Current lab members involved in this work are:

  • Diana Best
  • Marie Maclennan
  • James Crichton
  • Chris Playfoot
  • Abby Wilson
  • David Read

 

Genetic and Chromosomal Stability in Mammalian Germ Cells

Genome instability in the developing germline results in the transmission of new mutations and chromosomal changes into the next generation where they can cause developmental abnormalities, lethality, and human genetic disease. In particular, chromosomal aneuploidies, which arise at high frequencies in ageing human oocytes, are a leading cause of miscarriage and genetic diseases such as Down’s syndrome in human populations. Our research aims to characterise the pathways that promote genome stability in germ cells and pluripotent cells, thereby advancing our understanding of the basic biological mechanisms that cause human genetic disease.

 

Genes involved in defending the genome against the mutagenic activity of mobile genetic elements play a crucial role in maintaining genetic stability and in preventing aneuploidy in the germline. We have recently discovered a novel germline genome defence pathway that protects germ cells from endogenous retroviruses present in the genome, and helps to ensure that the correct number of chromosomes is transmitted to the next generation. We are currently using mice as a model system to investigate the consequences of failing to suppress mobile genetic elements in the germline, and to understand why mutations in germline genome defence genes lead to defects in meiosis in the developing germline. Currently, very little is known about cell type-specific regulation of chromosome segregation, and our research is aimed at advancing our understanding of the basic biological processes that can influence the rates of mutation and aneuploidy in mammalian sperm, eggs and embryos.

 

Purpose

To investigate molecular mechanisms involved in maintaining genetic and chromosomal stability in mammalian germ cells

 

Approach, Progress and Future Work

We use genetic manipulation in embryonic stem cells in order to investigate genes involved in germ cell function, and variety of techniques in genetics, biochemistry, developmental biology, bioinformatics, microscopy, and molecular and cell biology to study genetic and chromosomal stability using appropriate model systems.