Cans of worms …

Two recent reports from the Pubmed wires:

One report describes a global analysis of 3′-UTRs in C. elegans.  This group collected information on 3′-UTRs at different stages of development of the organism; this information came from data mining, cDNA and 3′-RACE sequencing, and 454 sequencing of 3′-end tags (to briefly summarize the approaches – read the paper to get a better flavor).  There is lots of information in the paper, but two things revisit issues that have been discussed in this blog.  One matter is that there is extensive alternative polyadenylation, such that mRNAs early in development are shorter longer than those later in development.  This is because of extensive alternative polyadenylation, and the result is recalls findings from similar studies in humans. It would seem as if, in animals at least, there is a global and important shift in poly(A) site choice during development.  The mechanism(s) underlying this shift remain an open question.

Second, there is no canonical poly(A) signal for many of the alternative polyadenylation sites that these authors see.  This is also similar to what is seen in humans, and recalls the more general themes of poly(A) signals that are discussed in this essay.  While no specifics can be stated, this suggests that the polyadenylation apparatus early in development is different, or that it is modified or regulated such that it has a different set of RNA sequence preferences.  It will be fascinating to see how these questions sort out.

A second report describes an interesting genetic screen that implicates a C. elegans homolog of the yeast polyadenylation factor subunit PFS2 in neural development. (Sorry for the link to Pubmed – the journal doesn’t yet have the link up.  Also, obviously, I am going by the abstract here.  If the paper raises additional issues, I will update this essay appropriately.)  This is interesting because the plant homolog of Pfs2, FY, has important regulatory functions in flowering and in chromatin-mediated gene silencing.  This raises the interesting (but highly speculative) possibility of an evolutionarily-conserved function for FY/PFS2.  It will be interesting to see if the C. elegans homolog plays analogous roles in chromatin modification.

The abstracts:

Science. 2010 Jun 3. [Epub ahead of print]

The Landscape of C. elegans 3’UTRs.

Mangone M, Manoharan AP, Thierry-Mieg D, Thierry-Mieg J, Han T, Mackowiak S, Mis E, Zegar C, Gutwein MR, Khivansara V, Attie O, Chen K, Salehi-Ashtiani K, Vidal
M, Harkins TT, Bouffard P, Suzuki Y, Sugano S, Kohara Y, Rajewsky N, Piano F, Gunsalus KC, Kim JK.

New York University, Center for Genomics & Systems Biology, Department of Biology, 1009 Silver Center, New York, NY 10003, USA.

Three-prime untranslated regions (3’UTRs) of metazoan mRNAs contain numerous regulatory elements, yet remain largely uncharacterized. Using polyA capture, 3’RACE, full-length cDNAs, and RNA-seq, we define ~26,000 distinct 3’UTRs in Caenorhabditis elegans for ~85% of the 18,328 experimentally supported protein coding genes and revise ~40% of gene models. Alternative 3’UTR isoforms are frequent, often differentially expressed during development. Average 3’UTR length decreases with animal age. Surprisingly, no polyadenylation signal (PAS) is detected for 13% of polyA sites, predominantly among shorter alternative isoforms. Trans-spliced (vs. non-trans-spliced) mRNAs possess longer 3’UTRs and frequently contain no PAS or variant PAS. We identify conserved 3’UTR motifs, isoform-specific predicted microRNA target sites, and polyadenylation of most histone genes. Our data reveal a rich complexity of 3’UTRs genome-wide and throughout development.

______________________________________________

Development. 2010 Jul;137(13):2237-50.

Nuclear pre-mRNA 3′-end processing regulates synapse and axon development in C.elegans.

Van Epps H, Dai Y, Qi Y, Goncharov A, Jin Y.

Division of Biological Sciences, Section of Neurobiology, University of California, San Diego, CA 92093, USA.

Nuclear pre-mRNA 3′-end processing is vital for the production of mature mRNA and the generation of the 3′ untranslated region (UTR). However, the roles and regulation of this event in cellular development remain poorly understood. Here,  we report the function of a nuclear pre-mRNA 3′-end processing pathway in synapse and axon formation in C. elegans. In a genetic enhancer screen for synaptogenesis mutants, we identified a novel polyproline-rich protein, Synaptic defective enhancer-1 (SYDN-1). Loss of function of sydn-1 causes abnormal synapse and axon  development, and displays striking synergistic interactions with several genes that regulate specific aspects of synapses. SYDN-1 is required in neurons and localizes to distinct regions of the nucleus. Through a genetic suppressor screen, we found that the neuronal defects of sydn-1 mutants are suppressed by loss of function in Polyadenylation factor subunit-2 (PFS-2), a conserved WD40-repeat protein that interacts with multiple subcomplexes of the pre-mRNA 3′-end processing machinery. PFS-2 partially colocalizes with SYDN-1, and SYDN-1 influences the nuclear abundance of PFS-2. Inactivation of several members of the nuclear 3′-end processing complex suppresses sydn-1 mutants. Furthermore, lack of sydn-1 can increase the activity of 3′-end processing. Our studies provide in vivo evidence for pre-mRNA 3′-end processing in synapse and axon development and identify SYDN-1 as a negative regulator of this cellular event in neurons.

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Edited on 6-23 to fix a mix-up that Clem caught.  Thanks.

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3 Responses to Cans of worms …

  1. Clem Weidenbenner says:

    Art:
    In the Science paper by Mangone et al. I read it that message length decreases with animal age… not that the messages get longer with age. Am I getting something mixed up?

  2. Clem Weidenbenner says:

    Ooops – forgot to acknowledge the ‘worms’ pun. Nicely done. Had to wiggle that into the conversation!

  3. Arthur Hunt says:

    Thanks for the heads-up, Clem. I corrected this mix-up.

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