Epidermal cells are generated during Caenorhabclitis elegans embryogenesis by several distinct lineage patterns. These patterns are controlled by maternal genes that determine the identities of early embryonic blastomeres. We show that the embryonicaUy expressed gene elt-1, which was shown previously to encode a GATA-Iike transcription factor, is required for the production of epidermal cells by each of these lineages. Depending on their lineage history, cells that become epidermal in wild-type embryos become either neurons or muscle cells in elt-1 mutant embryos. The ELT-1 protein is expressed in epidermal cells and in their precursors. We propose that elt-1 functions at an early step in the specification of epidermal cell fates.
RNA polymerase II (Pol II) transcription termination involves two linked processes: mRNA 3-end formation and release of Pol II from DNA. Signals for 3 processing are recognized by a protein complex that includes cleavage polyadenylation specificity factor (CPSF) and cleavage stimulation factor (CstF). Here we identify suppressors encoding proteins that play roles in processes at the 3 ends of genes by exploiting a mutation in which the 3 end of another gene is transposed into the first gene of the Caenorhabditis elegans lin-15 operon. As expected, genes encoding CPSF and CstF were identified in the screen. We also report three suppressors encoding proteins containing a domain that interacts with the C-terminal domain of Pol II (CID). We show that two of the CID proteins are needed for efficient 3 cleavage and thus may connect transcription termination with RNA cleavage. Furthermore, our results implicate a serine/arginine-rich (SR) protein, SRp20, in events following 3-end cleavage, leading to termination of transcription.Caenorhabditis elegans operon ͉ RNA polymerase II C-terminal domain ͉ SRp20 ͉ CTD T ermination of RNA polymerase II (Pol II)-mediated transcription plays an important role in gene regulation and involves two linked processes: 3Ј-end formation and release of the Pol II from the DNA (1). Accordingly, termination of Pol II requires both the presence of an intact 3Ј-processing signal and several 3Ј-end processing factors including the cleavage and polyadenylation specificity factor (CPSF) and the cleavage stimulation factor (CstF) (2-6). Several of the polyadenylation factors are associated with the C-terminal domain (CTD) of the largest subunit of Pol II, which is known to be required for efficient 3Ј processing (7-10). Much is known about what is required for 3Ј-end processing, but which factors specifically act in transcription termination and how these factors cause the Pol II complex to terminate are not entirely clear. The known link between 3Ј-end formation and transcription termination has led to multiple models to explain transcription termination.Two such models have been proposed to explain the connection between 3Ј-end processing and transcription termination. One model, known as the ''allosteric'' model, proposes that termination is triggered by a conformational change of the Pol II complex that occurs on the emergence of the polyadenylation sequences (3). Another model, known as the ''torpedo'' model, proposes that termination is triggered subsequent to the cleavage event by the exonuclease XRN-2. When cleavage occurs at the poly(A) polymerase site, Pol II continues to transcribe a now-uncapped downstream RNA. This RNA is subject to degradation by the 5Ј-3Ј exonuclease XRN-2; according to the torpedo model, termination occurs when the exonuclease collides with Pol II (11-13). Recently, a unified allosteric-torpedo model has been proposed to explain new experimental evidence in support of both the earlier models (14,15).One commonality between the three models of termination is the obl...
Down syndrome (DS) is the most common genetic cause of intellectual disability (ID) in humans with an incidence of ∼1:1,000 live births worldwide. It is caused by the presence of an extra copy of all or a segment of the long arm of human chromosome 21 (trisomy 21). People with DS present with a constellation of phenotypic alterations involving most organs and organ systems. ID is present in all people with DS, albeit with variable severity. DS is also the most frequent genetic cause of Alzheimer's disease (AD), and ∼50% of those with DS will develop AD-related dementia. In the last few years, significant progress has been made in understanding the crucial genotype-phenotype relationships in DS, in identifying the alterations in molecular pathways leading to the various clinical conditions present in DS, and in preclinical evaluations of potential therapies to improve the overall health and well-being of individuals with DS. In June 2015, 230 scientists, advocates, patients, and family members met in Paris for the 1st International Conference of the Trisomy 21 Research Society. Here, we report some of the most relevant presentations that took place during the meeting.
In trans-splicing, the pre-mRNA products of two different genes are spliced together to form a single, mature mRNA. In one type oE Lrans-splicing, prc-mRNAs of many different genes receive a single, short leader, called spliced leader or SL (diagrammed in Fig. 1 and reviewed in refs. 1-3). This type of trans-splicing was first discovered in the primitive eukaryotes, the trypanosomes, where it is apparcntly the only kind of nuclear mRNA s p l i~i n g '~.~) .Subsequently, it was discovered in nematodes (round trematodes (flat worms) (7), and euglena@'. Although this type of trans-splicing has never been found in any of the other well-studied organisms. Bruzik and Maniatis(9) have recently reported that mammalian cells are capable of perforining the reaction when they are provided with the appropriate pre-mRNAs.In the worms, trans-splicing co-exists with normal, or cissplicing, in which introns are removed from the pre-mRNAs. The same pre-mRNAs undergo both types of splicing. The SLs, which range from 22 nucleotides in nematodes to 39 nt in trypanosomes, are donated by 100-150 nt RNAs, called SL RNAs (Fig. 1). These RNAs exist in the cell in the form of snRNPs: they have characteristic stem-loop structures, with 5' modified caps, and are bound to the same proteins that are bound to U1, U2, U4/Ub and US RNAS"~-'~). The transsplicing reaction is closely related to cis-splicing: it is catalyzcd by the same snRNPs that catalyze cis-splicing(l3>l4); the donor site on the SL FWA matches the cis-splicing con-sensusc6,15); the trans-splicc acceptor sites on thc prc-mRNAs are indistinguishable from intron 3' splice sites; and equivalent branched intermediates form in trans-and cis-
Pulmonary disease, lower respiratory tract infection, and pneumonia are the largest causes of morbidity and mortality in individuals with Down syndrome (DS), but whether pulmonary diagnoses in children with DS are common and occur independently of cardiac disease and pulmonary hypertension (PH) is unknown. Cardiopulmonary phenotypes were examined in a cohort of 1248 children with DS. Aptamer-based proteomic analysis of blood was performed in a subset (n = 120) of these children. By the age of 10 years, half of the patients in this cohort (n = 634, 50.8%) had co-occurring pulmonary diagnoses. That proteins and related pathways were distinct between children with pulmonary diagnoses and those with cardiac disease and/or PH may indicate that pulmonary diagnoses appear to occur independently of cardiac disease and PH. Heparin sulfate-glycosaminoglycandegradation, nicotinate metabolism, and elastic fiber formation were ranked highest in the group with pulmonary diagnoses.
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