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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM030702-31
Application #
8197652
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Carter, Anthony D
Project Start
1982-09-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
31
Fiscal Year
2012
Total Cost
$534,268
Indirect Cost
$171,804
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Maxwell, Colin S; Kruesi, William S; Core, Leighton J et al. (2014) Pol II docking and pausing at growth and stress genes in C. elegans. Cell Rep 6:455-66
Farboud, Behnom; Nix, Paola; Jow, Margaret M et al. (2013) Molecular antagonism between X-chromosome and autosome signals determines nematode sex. Genes Dev 27:1159-78
Pferdehirt, Rebecca R; Meyer, Barbara J (2013) SUMOylation is essential for sex-specific assembly and function of the Caenorhabditis elegans dosage compensation complex on X chromosomes. Proc Natl Acad Sci U S A 110:E3810-9
Wood, Andrew J; Lo, Te-Wen; Zeitler, Bryan et al. (2011) Targeted genome editing across species using ZFNs and TALENs. Science 333:307
Meyer, Barbara J (2010) Targeting X chromosomes for repression. Curr Opin Genet Dev 20:179-89
Wood, Andrew J; Severson, Aaron F; Meyer, Barbara J (2010) Condensin and cohesin complexity: the expanding repertoire of functions. Nat Rev Genet 11:391-404
Mets, David G; Meyer, Barbara J (2009) Condensins regulate meiotic DNA break distribution, thus crossover frequency, by controlling chromosome structure. Cell 139:73-86
Csankovszki, Gyorgyi; Collette, Karishma; Spahl, Karin et al. (2009) Three distinct condensin complexes control C. elegans chromosome dynamics. Curr Biol 19:9-19
Jans, Judith; Gladden, John M; Ralston, Edward J et al. (2009) A condensin-like dosage compensation complex acts at a distance to control expression throughout the genome. Genes Dev 23:602-18
Tsai, Chun J; Mets, David G; Albrecht, Michael R et al. (2008) Meiotic crossover number and distribution are regulated by a dosage compensation protein that resembles a condensin subunit. Genes Dev 22:194-211

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