ANALYSIS OF NEMATODE SEX DETERMINATION

Summary

Principal Investigator: Barbara J Meyer
Abstract: DESCRIPTION (provided by applicant): Dose-sensitive signals play essential roles in cell fate decisions during development. One area of our research investigates mechanisms by which small quantitative differences in molecular signals are translated into dramatically different developmental fates. One of our long-term goals is to dissect the quantitative signals and the genetic switch that specifies sexual fate in the nematode C. elegans. C. elegans determines sex by tallying X-chromosome number relative to the ploidy, the sets of autosomes (X:A signal). We showed that a set of genes on X, called X signal elements (XSEs), relays X-chromosome dose by repressing the activity of the sex determination switch gene xol-1 through both transcriptional and pre-mRNA mechanisms. Another set of genes called autosomal signal elements (ASEs) communicates ploidy by antagonizing the XSEs to activate xol-1. xol-1 specifies the male fate when active and the hermaphrodite fate when inactive. Our work investigates molecular mechanisms by which XSEs and ASEs antagonize each other to determine sex. One XSE is a nuclear hormone receptor (NHR) called SEX-1, a homolog of the retinoic acid receptor (RAR) gene family that participates in signaling pathways used for patterning and cellular differentiation in all metazoans. Disruptions in RARs are associated with human cancers, knowledge that has lead to the use of retinoids in the treatment of leukemias. Information gained from model organisms such as C. elegans about the genetic pathways in which NHRs function will provide an opportunity to discover other gene targets for drug therapy, which might be applicable to humans. A second long-term goal is understand the mechanism of X-chromosome dosage compensation, which equalizes X expression between the sexes. We defined a protein complex (DCC) that binds both X chromosomes of XX animals to repress X expression by half. Members of the complex also play essential roles in the compaction, resolution, and segregation of mitotic and meiotic chromosomes as well as the control of genetic recombination between homologous meiotic chromosomes. Not only is the protein complex essential for proper gene expression and viability, most components are essential for genome stability. Thus, studying dosage compensation will help us understand genomic instability caused by errors in chromosome segregation and disruption of meiotic recombination. We have identified cis-acting regulatory elements that target the X chromosome for repression by the DCC and discovered fundamental principles by which the DCC recognizes and binds X. Our future work will explore the connection between chromosome structure, DCC binding, and chromosome-wide gene repression. PUBLIC HEALTH RELEVANCE: A protein we found to be pivotal for sex determination in the round worm C. elegans is a homolog of the retinoic acid receptor (RAR) gene family that participates in signaling pathways used for patterning and cellular differentiation in all metazoans. Disruptions in RARs are associated with human cancers, knowledge that has lead to the use of retinoids in the treatment of leukemias. Information gained from model organisms such as C. elegans about the genetic pathways in which NHRs function will provide an opportunity to discover other gene targets for drug therapy, which might be applicable to humans. In addition, we have discovered protein complexes with shared components that participate in many chromosome behaviors including chromosome-wide gene regulation through dosage compensation, mitotic chromosome segregation, and the control of meiotic chromosome recombination. Disruption of these proteins causes severe chromosome segregation defects and genomic instability. Examination of tumors invariably reveals the genome to be rearranged and aneuploid, showing the significant role chromosome instability plays in generating cancerous cells. Our protein complexes give us insight into the mechanisms underlying the genome rearrangements associated with such a cancerous state.
Funding Period: 1982-09-01 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. pmc Sperm chromatin proteomics identifies evolutionarily conserved fertility factors
    Diana S Chu
    Department of Biology, 1600 Holloway Avenue, San Francisco State University, San Francisco, California 94132, USA
    Nature 443:101-5. 2006
  2. pmc SUMOylation is essential for sex-specific assembly and function of the Caenorhabditis elegans dosage compensation complex on X chromosomes
    Rebecca R Pferdehirt
    Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 3204
    Proc Natl Acad Sci U S A 110:E3810-9. 2013
  3. pmc Precise and heritable genome editing in evolutionarily diverse nematodes using TALENs and CRISPR/Cas9 to engineer insertions and deletions
    Te Wen Lo
    Howard Hughes Medical Institute, University of California, Berkeley, California 94720
    Genetics 195:331-48. 2013
  4. pmc Molecular antagonism between X-chromosome and autosome signals determines nematode sex
    Behnom Farboud
    Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA
    Genes Dev 27:1159-78. 2013
  5. pmc Targeted genome editing across species using ZFNs and TALENs
    Andrew J Wood
    Howard Hughes Medical Institute HHMI, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 3204, USA
    Science 333:307. 2011
  6. pmc An MLL/COMPASS subunit functions in the C. elegans dosage compensation complex to target X chromosomes for transcriptional regulation of gene expression
    Rebecca R Pferdehirt
    Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, California 94720, USA
    Genes Dev 25:499-515. 2011
  7. pmc Condensin and cohesin complexity: the expanding repertoire of functions
    Andrew J Wood
    Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California 94720 3204, USA
    Nat Rev Genet 11:391-404. 2010
  8. pmc Targeting X chromosomes for repression
    Barbara J Meyer
    HHMI and U C Berkeley, Department of Molecular and Cell Biology, Berkeley, CA 94720 3704, United States
    Curr Opin Genet Dev 20:179-89. 2010
  9. pmc Condensins regulate meiotic DNA break distribution, thus crossover frequency, by controlling chromosome structure
    David G Mets
    Howard Hughes Medical Institute, University of California Berkeley, Berkeley, CA 94720 3204, USA
    Cell 139:73-86. 2009
  10. pmc A condensin-like dosage compensation complex acts at a distance to control expression throughout the genome
    Judith Jans
    Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 97420, USA
    Genes Dev 23:602-18. 2009

Research Grants

Detail Information

Publications16

  1. pmc Sperm chromatin proteomics identifies evolutionarily conserved fertility factors
    Diana S Chu
    Department of Biology, 1600 Holloway Avenue, San Francisco State University, San Francisco, California 94132, USA
    Nature 443:101-5. 2006
    ..Our list therefore provides significant opportunity to identify causes of male infertility and targets for male contraceptives...
  2. pmc SUMOylation is essential for sex-specific assembly and function of the Caenorhabditis elegans dosage compensation complex on X chromosomes
    Rebecca R Pferdehirt
    Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 3204
    Proc Natl Acad Sci U S A 110:E3810-9. 2013
    ..Our results reinforce a newly emerging theme in which multiple proteins of a complex are collectively SUMOylated in response to a specific stimulus, leading to accelerated complex formation and enhanced function. ..
  3. pmc Precise and heritable genome editing in evolutionarily diverse nematodes using TALENs and CRISPR/Cas9 to engineer insertions and deletions
    Te Wen Lo
    Howard Hughes Medical Institute, University of California, Berkeley, California 94720
    Genetics 195:331-48. 2013
    ....
  4. pmc Molecular antagonism between X-chromosome and autosome signals determines nematode sex
    Behnom Farboud
    Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA
    Genes Dev 27:1159-78. 2013
    ..Ironically, while the recent work of others showed that the fly sex signal does not fit this simple paradigm, our work shows that the worm signal does...
  5. pmc Targeted genome editing across species using ZFNs and TALENs
    Andrew J Wood
    Howard Hughes Medical Institute HHMI, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 3204, USA
    Science 333:307. 2011
    ....
  6. pmc An MLL/COMPASS subunit functions in the C. elegans dosage compensation complex to target X chromosomes for transcriptional regulation of gene expression
    Rebecca R Pferdehirt
    Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, California 94720, USA
    Genes Dev 25:499-515. 2011
    ..We also show that the DCC balances X-chromosome gene expression between sexes by controlling transcription...
  7. pmc Condensin and cohesin complexity: the expanding repertoire of functions
    Andrew J Wood
    Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California 94720 3204, USA
    Nat Rev Genet 11:391-404. 2010
    ..Emerging data are expanding the range of processes in which condensin and cohesin are known to participate and are enhancing our knowledge of how chromosome architecture is regulated to influence numerous cellular functions...
  8. pmc Targeting X chromosomes for repression
    Barbara J Meyer
    HHMI and U C Berkeley, Department of Molecular and Cell Biology, Berkeley, CA 94720 3704, United States
    Curr Opin Genet Dev 20:179-89. 2010
    ..The reshuffling of interchangeable molecular parts creates independent machines with similar architecture but distinct biological functions...
  9. pmc Condensins regulate meiotic DNA break distribution, thus crossover frequency, by controlling chromosome structure
    David G Mets
    Howard Hughes Medical Institute, University of California Berkeley, Berkeley, CA 94720 3204, USA
    Cell 139:73-86. 2009
    ....
  10. pmc A condensin-like dosage compensation complex acts at a distance to control expression throughout the genome
    Judith Jans
    Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 97420, USA
    Genes Dev 23:602-18. 2009
    ..DCC disruption causes opposite effects on expression of X and autosomal genes. The DCC thus acts at a distance to impact expression throughout the genome...
  11. pmc Three distinct condensin complexes control C. elegans chromosome dynamics
    Gyorgyi Csankovszki
    Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
    Curr Biol 19:9-19. 2009
    ..Instead, its condensin I-like complex (here called condensin I(DC)) dampens gene expression along hermaphrodite X chromosomes during dosage compensation...
  12. pmc Meiotic crossover number and distribution are regulated by a dosage compensation protein that resembles a condensin subunit
    Chun J Tsai
    Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 97420, USA
    Genes Dev 22:194-211. 2008
    ..We propose that both processes utilize a related mechanism involving changes in higher-order chromosome structure to achieve chromosome-wide effects...
  13. pmc Revisiting the X:A signal that specifies Caenorhabditis elegans sexual fate
    John M Gladden
    Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, California 94720 3204, USA
    Genetics 177:1639-54. 2007
    ..Prior to the onset of dosage compensation, the difference in XSE expression between XX and XO embryos appears to be greater than twofold, making X chromosome counting a robust process...
  14. pmc A ONECUT homeodomain protein communicates X chromosome dose to specify Caenorhabditis elegans sexual fate by repressing a sex switch gene
    John M Gladden
    Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, California 94720 3204, USA
    Genetics 177:1621-37. 2007
    ..hermaphrodite fate by the synergistic action of multiple, independent XSEs that render xol-1 active or inactive, primarily through transcriptional regulation...
  15. pmc Clustered DNA motifs mark X chromosomes for repression by a dosage compensation complex
    Patrick McDonel
    Howard Hughes Medical Institute, University of California Berkeley, 16 Barker Hall, Berkeley, California 94720 3204, USA
    Nature 444:614-8. 2006
    ..Thus, X-specific repression is established through sequences not specific to X. The distribution of common motifs provides the foundation for repression along an entire chromosome...
  16. pmc Pol II docking and pausing at growth and stress genes in C. elegans
    Colin S Maxwell
    Department of Biology, Duke Center for Systems Biology, Duke University, Durham, NC 27708, USA
    Cell Rep 6:455-66. 2014
    ..Our work suggests that growth and stress genes are both regulated postrecruitment during starvation but at initiation and elongation, respectively, coordinating gene expression with nutrient availability. ..

Research Grants30

  1. Regulation of chromosome segregation by SMC complexes and Top2 in S. pombe
    MATTHEW J O'CONNELL; Fiscal Year: 2013
    ..This project studies proteins that are essential for accurate inheritance of chromosomes as cells divide. The public health relevance is thus central to the biology of cancer and aging. ..