Rho kinase paralog regulation of gene transcription
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE34769 | GEO | 2012/06/01
SECONDARY ACCESSION(S): PRJNA150351
REPOSITORIES: GEO
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Project description:Gene duplication enables the emergence of new functions by lowering the general evolutionary pressure. Previous studies have highlighted the role of specific paralog genes during cell differentiation, e.g., in chromatin remodeling complexes. It remains unexplored whether similar mechanisms extend to other biological functions and whether the regulation of paralog genes is conserved across species. Here, we analyze the expression of paralogs across human tissues, during development and neuronal differentiation in fish, rodents and humans. While ~80% of paralog genes are co-regulated, a subset of paralogs shows divergent expression profiles, contributing to variability of protein complexes. We identify 78 substitutions of paralog pairs that occur during neuronal differentiation and are conserved across species. Among these, we highlight a substitution between the paralogs Sec23a and Sec23b subunits of the COPII complex. Altering the ratio between these two genes via RNAi-mediated knockdown is sufficient to influence the differentiation of immature neuron. We propose that remodeling of the vesicular transport system via paralog substitutions is an evolutionary conserved mechanism enabling neuronal differentiation.
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Project description:Gene duplication enables the emergence of new functions by lowering the general evolutionary pressure. Previous studies have highlighted the role of specific paralog genes during cell differentiation, e.g., in chromatin remodeling complexes. It remains unexplored whether similar mechanisms extend to other biological functions and whether the regulation of paralog genes is conserved across species. Here, we analyze the expression of paralogs across human tissues, during development and neuronal differentiation in fish, rodents and humans. While ~80% of paralog genes are co-regulated, a subset of paralogs shows divergent expression profiles, contributing to variability of protein complexes. We identify 78 substitutions of paralog eggNOG pairs that occur during neuronal differentiation and are conserved across species. Among these, we highlight a substitution between the paralogs Sec23a and Sec23b subunits of the COPII complex. Altering the ratio between these two genes via silencing-RNA knockdown was able to influence neuronal differentiation in different ways. We propose that remodeling of the vesicular transport system via paralog substitutions is an evolutionary conserved mechanism enabling neuronal differentiation.
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Project description:Gene duplication enables the emergence of new functions by lowering the general evolutionary pressure. Previous studies have highlighted the role of specific paralog genes during cell differentiation, e.g., in chromatin remodeling complexes. It remains unexplored whether similar mechanisms extend to other biological functions and whether the regulation of paralog genes is conserved across species. Here, we analyze the expression of paralogs across human tissues, during development and neuronal differentiation in fish, rodents and humans. While ~80% of paralog genes are co-regulated, a subset of paralogs shows divergent expression profiles, contributing to variability of protein complexes. We identify 78 substitutions of paralog eggNOG pairs that occur during neuronal differentiation and are conserved across species. Among these, we highlight a substitution between the paralogs Sec23a and Sec23b subunits of the COPII complex. Altering the ratio between these two genes via silencing-RNA knockdown was able to influence neuronal differentiation in different ways. We propose that remodeling of the vesicular transport system via paralog substitutions is an evolutionary conserved mechanism enabling neuronal differentiation.
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Project description:CRISPR knockout screens have accelerated the discovery of important cancer genetic dependencies. However, traditional CRISPR-Cas9 screens are limited in their ability to assay the function of redundant or duplicated genes. Paralogs in multi-gene families constitute two-thirds of the protein-coding genome, so this blind spot is the rule, not the exception. To overcome the limitations of single gene CRISPR knockout screens, we developed paired guide RNAs for Paralog gENetic interaction mapping (pgPEN), a pooled CRISPR/Cas9 approach which targets over a thousand duplicated human paralogs in single knockout and double knockout configurations. We applied pgPEN to two cell lineages and discovered that over 10% of human paralogs exhibit synthetic lethality in at least one cellular context. We recovered known synthetic lethal paralogs such as MAP2K1/MAP2K2, important drug targets such as CDK4/CDK6, and numerous other synthetic lethal pairs such as CCNL1/CCNL2. In addition, we identified ten tumor suppressive paralog pairs whose compound loss promotes cell growth. These findings identify a large number of previously unidentified essential gene families and nominate new druggable targets for oncology drug discovery.
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Project description:cDNA microarrays have become the technology of choice for profiling the expression of thousands of genes simultaneously in a single sample. However, cross-hybridization between targets and probes that do not correspond must be considered carefully during the design, analysis, and interpretation of these experiments. Here, we examined this potentially confounding issue by competitively hybridizing fragments with similar sequence obtained from two paralogous genes to a custom cDNA microarray that contains probes for only one of these two genes. We found that although a large contiguous portion of these two fragments was 84% identical and only one target was represented on the array, there was very little cross-hybridization of the non-represented target to either the paralogous probes or other (non-similar) features. We conclude that cDNA microarrays are indeed very specific and that promiscuous paralog hybridization adds little noise to the data. More generally, the absence of specific probes for any given gene does not increase the chance for cross-hybridization between non-specific probes and targets, even if sequence similarity is relatively high. PCR products from two paralogs (arginine vasotocin/vasopressin and isotocin/mesotocin/oxytocin) were competitively hybridized onto a glass cDNA microarray platform of the same species. The platform contained probes for only one of the two paralogs in an effort to assess cross-hybridization between paralogous targets and probes.
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Project description:The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct, remains controversial. We addressed this longstanding question in primary CD4+ 'helper' T cells, the principal orchestrators of adaptive immunity. Using a combination of genetic and genomic approaches, we demonstrate that, although both influence regulatory (Treg) and effector T cell responses, and control many of the same genes, they are not functionally equivalent and, in fact, only the latter is required for immunological tolerance. Differences in genomic distribution and transcriptomic output support the conclusion that STAT5B is dominant and, surprisingly, point towards relative abundance (i.e. paralog dose), rather than unique functional capabilities, as the principal distinguishing feature. Collectively, our data provide a unifying model for the discrete and redundant activities of STAT5A and STAT5B, establishing that asymmetrical expression underlies paralog specificity (or dominance) in the face of widespread structural homology. This dataset includes 55 individual samples of transcriptome or STAT5 distibution data from cytokine treated CD4+T cells. Each culture condition includes at least 2 biological replicates per genotype.
2016-03-28 | E-GEOD-77656 | biostudies-arrayexpress