Abstract
Despite having been sequenced over a decade ago, the functional significance of much of the mammalian genome remains unknown. The mouse has become the preeminent mammalian model for identifying endogenous gene function in vivo. Here we characterize the phenotype of a loss-of function allele for the evolutionarily conserved transcription factor, Elongation Factor Homolog 1 (Elof1). Recent work utilizing the yeast homolog, Elf1, has demonstrated that Elf1 associates with the RNA polymerase II complex to promote elongation by relieving the association of the template DNA strand with bound histones. Loss of Elof1 results in developmental delay and morphological defects during early mouse development resulting in peri-gastrulation lethality. Although Elof1 is highly conserved we observe tissue specific expression during gastrulation and in adult murine tissues, suggesting there may be other genes with similar function in diverse tissues or that mElof1 has adopted lineage specific functions. To better understand its function in mammalian transcription, we examined splice variants and find that Elof1 regulates mutually exclusive exon use in vivo. Distinct from what has been demonstrated in yeast, we demonstrate that Elof1 is essential for viability during mammalian gastrulation which may be due to a role mediating tissue specific exclusive exon use, a regulatory function unique to higher eukaryotes.
Highlights
The task of evaluating the function of every gene is daunting, the International Mouse Phenotyping Consortium has made significant headway
Other representative structures include the notochord, an axial midline structure that extends from the node to the prechordal plate at the anterior end of the embryo, headfolds which are produced by the anterior ectoderm and the embryonic mesoderm-derived allantois that projects from the posterior end of the primitive streak into the extra-embryonic cavity
Morphological and histological analyses of Elongation Factor Homolog 1 (Elof1)-deficient embryos indicate a failure to initiate gastrulation. These observations are supported by the lack of normal developmental hallmarks and additional defects including failure to initiate T expression, reduced embryonic proliferation and a population of distally positioned but abnormally rounded cells. Together these results demonstrate that murine Elof1, unlike yeast Elongation factor 1 (Elf1), is critical for viability and suggests that this highly conserved component of the RNA polymerase II (RNApII) elongation complex has acquired additional essential functions throughout evolution
Summary
The task of evaluating the function of every gene is daunting, the International Mouse Phenotyping Consortium has made significant headway (www.mousephenotype.org). Modified mice currently provide the best model to gain insight into functional role of individual genes in the mammalian genome. Thirty percent of knockout genes result in embryonic lethality, which offers opportunities to study the function of essential genes during mammalian development. We are currently engaged in a large-scale evaluation of early embryonic lethal alleles generated by the Knockout Mouse Project (KOMP). One class of proteins crucial to mammalian development and survival are transcription factors, which can control when, where, and at what rate genes are expressed in diverse tissues. Elongation factors are a subclass of transcriptional regulators that interact with RNA polymerase II (RNApII) to aid in lengthening the growing RNA chain as well as to promote proper
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