The long-term objectives of my research team are to understand cell fate decisions, with emphasis on the fundamental and deeply conserved germ versus soma decision. Germ cells must remain totipotent and immortal in order to produce eggs and sperm and entire new organism's generation after generation, while somatic cells must lose those properties in order to serve their specialized roles during the finite life of an organism. W seek to elucidate mechanisms that specify germ cells, protect germline fate in those cells, and antagonize germline fate in somatic cells. Our studies combine powerful genetic, genomic, and molecular approaches in the model system Caenorhabditis elegans. My research group has established new paradigms for how the germ-soma decision is regulated. We found that during embryogenesis, the chromatin regulator MES-4 epigenetically transmits the 'memory of germline'from parental to progeny germ cells. MES-4 can promote germline development even in somatic cells of embryos, but the synMuv B chromatin regulators antagonize germline fate in the soma. At later stages, as germ cells develop, germline-specific 'germ granules'protect germline fate by antagonizing somatic fate.
The specific aims of this proposal are to elucidate the underlying mechanisms by which MES- 4 promotes germline fate, synMuv B proteins antagonize germline fate, and germ granules protect germline fate.
In Aim 1, we will test if transcription in the maternal germ line is necessary and sufficient to initiate MES-4 marking of genes, if MES-4 marking is propagated during embryogenesis by MES-4 binding the chromatin modifications that it generates, and if MES-4's essential role in the primordial germ cells is to guide establishment of the proper program of gene expression.
In Aim 2, we will analyze the locations of synMuv B factors compared to MES-4 across the genome in embryos, and determine whether synMuv B factors block expression of germline genes in somatic cells by altering MES-4 marking of genes or by altering global chromatin organization in somatic cells.
In Aim 3, we will test our model that adult germ cells occasionally misexpress somatic transcripts and that germ granules protect germline fate by repressing translation of those transcripts, and we will determine whether germ cells that lack germ granules resemble mammalian teratomas and can develop into a variety of somatic cell types in addition to neurons. Germ cells and stem cells share the special properties of immortality and pluripotency, and both are targets of regenerative medicine. The ability to harness the proliferative potential of germ and stem cells and direct them to develop into desired tissues requires knowledge of factors and mechanisms that promote appropriate cell fate decisions and that block inappropriate cell fate decisions. Our proposed studies in C. elegans wil reveal how germ cell fate is specified, protected, and antagonized by factors and processes that are conserved across species.

Public Health Relevance

This proposal uses powerful genetic, genomic, and molecular approaches in a model animal system to investigate how cells are instructed to develop along appropriate pathways. We focus on the fundamental and deeply conserved cell fate decision whether to develop as reproductive 'germ cells'or non-reproductive 'somatic cells', and we study factors that promote appropriate developmental decisions and factors that block inappropriate developmental decisions. Our findings will contribute to understanding how defects in control of cell fates contribute to cancer and how the special properties of germ cells and stem cells can be harnessed in regenerative medicine.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034059-28
Application #
8668976
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Haynes, Susan R
Project Start
1984-09-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
28
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Santa Cruz
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
Knutson, Andrew Kek?pa'a; Egelhofer, Thea; Rechtsteiner, Andreas et al. (2017) Germ Granules Prevent Accumulation of Somatic Transcripts in the Adult Caenorhabditis elegans Germline. Genetics 206:163-178
Kaneshiro, Kiyomi R; Strome, Susan (2017) Inheritance of protection from osmotic stress. Nat Cell Biol 19:151-152
Ahn, Jeong H; Rechsteiner, Andreas; Strome, Susan et al. (2016) A Conserved Nuclear Cyclophilin Is Required for Both RNA Polymerase II Elongation and Co-transcriptional Splicing in Caenorhabditis elegans. PLoS Genet 12:e1006227
Marceau, Aimee H; Felthousen, Jessica G; Goetsch, Paul D et al. (2016) Structural basis for LIN54 recognition of CHR elements in cell cycle-regulated promoters. Nat Commun 7:12301
Garrigues, Jacob M; Sidoli, Simone; Garcia, Benjamin A et al. (2015) Defining heterochromatin in C. elegans through genome-wide analysis of the heterochromatin protein 1 homolog HPL-2. Genome Res 25:76-88
Strome, Susan; Updike, Dustin (2015) Specifying and protecting germ cell fate. Nat Rev Mol Cell Biol 16:406-16
Rahman, Mohammad M; Munzig, Mandy; Kaneshiro, Kiyomi et al. (2015) Caenorhabditis elegans polo-like kinase PLK-1 is required for merging parental genomes into a single nucleus. Mol Biol Cell 26:4718-35
Latorre, Isabel; Chesney, Michael A; Garrigues, Jacob M et al. (2015) The DREAM complex promotes gene body H2A.Z for target repression. Genes Dev 29:495-500
Gaydos, Laura J; Wang, Wenchao; Strome, Susan (2014) Gene repression. H3K27me and PRC2 transmit a memory of repression across generations and during development. Science 345:1515-8
Strome, Susan; Kelly, William G; Ercan, Sevinc et al. (2014) Regulation of the X chromosomes in Caenorhabditis elegans. Cold Spring Harb Perspect Biol 6:

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