Prof. Yuval Tabach

Proteins that function in the same pathways, protein complexes or the same
environmental conditions can show similar patterns of sequence conservation across
phylogenetic clades. In species that no longer require a specific protein complex or pathway,
these proteins, as a group, tend to be lost or diverge. Analysis of the similarity in patterns of
sequence conservation across a large set of eukaryotes can predict functional associations
between different proteins, identify… Show more

Proteins that function in the same pathways, protein complexes or the same
environmental conditions can show similar patterns of sequence conservation across
phylogenetic clades. In species that no longer require a specific protein complex or pathway,
these proteins, as a group, tend to be lost or diverge. Analysis of the similarity in patterns of
sequence conservation across a large set of eukaryotes can predict functional associations
between different proteins, identify new pathway members and reveal the function of ... Show less

Myotonic dystrophy disorders are caused by expanded CUG repeats in noncoding regions. Here we used Caenorhabditis elegans expressing CUG repeats to identify genes that modulate the toxicity of such repeats. We identified 15 conserved genes that function as suppressors or enhancers of CUG repeat-induced toxicity and that modulate formation of nuclear foci by CUG-repeat RNA. These genes regulate CUG repeat-induced toxicity through distinct mechanisms including RNA export and clearance, thus… Show more

Myotonic dystrophy disorders are caused by expanded CUG repeats in noncoding regions. Here we used Caenorhabditis elegans expressing CUG repeats to identify genes that modulate the toxicity of such repeats. We identified 15 conserved genes that function as suppressors or enhancers of CUG repeat-induced toxicity and that modulate formation of nuclear foci by CUG-repeat RNA. These genes regulate CUG repeat-induced toxicity through distinct mechanisms including RNA export and clearance, thus suggesting that CUG-repeat toxicity is mediated by multiple pathways. A subset of the genes are also involved in other degenerative disorders. The nonsense-mediated mRNA decay (NMD) pathway has a conserved role in regulating CUG-repeat-RNA transcript levels and toxicity, and NMD recognition of toxic RNAs depends on 3'-untranslated-region GC-nucleotide content. Our studies suggest a broader surveillance role for NMD in which variations in this pathway influence multiple degenerative diseases. Show less

N 6-methyladenosine (m 6 A) is the most ubiquitous mRNA base modification, but
little is known about its precise location, temporal dynamics, and regulation. Here, we
generated genomic maps of m 6 A sites in meiotic yeast transcripts at nearly single-
nucleotide resolution, identifying 1,308 putatively methylated sites within 1,183 transcripts.
We validated eight out of eight methylation sites in different genes with direct genetic
analysis, demonstrated that methylated sites… Show more

N 6-methyladenosine (m 6 A) is the most ubiquitous mRNA base modification, but
little is known about its precise location, temporal dynamics, and regulation. Here, we
generated genomic maps of m 6 A sites in meiotic yeast transcripts at nearly single-
nucleotide resolution, identifying 1,308 putatively methylated sites within 1,183 transcripts.
We validated eight out of eight methylation sites in different genes with direct genetic
analysis, demonstrated that methylated sites are significantly conserved in a related ... Show less

Genes with common profiles of the presence and absence in disparate genomes tend to function in the same pathway. By mapping all human genes into about 1000 clusters of genes with similar patterns of conservation across eukaryotic phylogeny, we determined that sets of genes associated with particular diseases have similar phylogenetic profiles. By focusing on those human phylogenetic gene clusters that significantly overlap some of the thousands of human gene sets defined by their coexpression… Show more

Genes with common profiles of the presence and absence in disparate genomes tend to function in the same pathway. By mapping all human genes into about 1000 clusters of genes with similar patterns of conservation across eukaryotic phylogeny, we determined that sets of genes associated with particular diseases have similar phylogenetic profiles. By focusing on those human phylogenetic gene clusters that significantly overlap some of the thousands of human gene sets defined by their coexpression or annotation to pathways or other molecular attributes, we reveal the evolutionary map that connects molecular pathways and human diseases. The other genes in the phylogenetic clusters enriched for particular known disease genes or molecular pathways identify candidate genes for roles in those same disorders and pathways. Focusing on proteins coevolved with the microphthalmia-associated transcription factor (MITF), we identified the Notch pathway suppressor of hairless (RBP-Jk/SuH) transcription factor, and showed that RBP-Jk functions as an MITF cofactor.
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Genetic and biochemical analyses of RNA interference (RNAi) and microRNA (miRNA) pathways have revealed proteins such as Argonaute and Dicer as essential cofactors that process and present small RNAs to their targets. Well-validated small RNA pathway cofactors such as these show distinctive patterns of conservation or divergence in particular animal, plant, fungal and protist species. We compared 86 divergent eukaryotic genome sequences to discern sets of proteins that show similar phylogenetic… Show more

Genetic and biochemical analyses of RNA interference (RNAi) and microRNA (miRNA) pathways have revealed proteins such as Argonaute and Dicer as essential cofactors that process and present small RNAs to their targets. Well-validated small RNA pathway cofactors such as these show distinctive patterns of conservation or divergence in particular animal, plant, fungal and protist species. We compared 86 divergent eukaryotic genome sequences to discern sets of proteins that show similar phylogenetic profiles with known small RNA cofactors. A large set of additional candidate small RNA cofactors have emerged from functional genomic screens for defects in miRNA- or short interfering RNA (siRNA)-mediated repression in Caenorhabditis elegans and Drosophila melanogaster1, 2, and from proteomic analyses of proteins co-purifying with validated small RNA pathway proteins3, 4. The phylogenetic profiles of many of these candidate small RNA pathway proteins are similar to those of known small RNA cofactor proteins. We used a Bayesian approach to integrate the phylogenetic profile analysis with predictions from diverse transcriptional coregulation and proteome interaction data sets to assign a probability for each protein for a role in a small RNA pathway. Testing high-confidence candidates from this analysis for defects in RNAi silencing, we found that about one-half of the predicted small RNA cofactors are required for RNAi silencing. Many of the newly identified small RNA pathway proteins are orthologues of proteins implicated in RNA splicing. In support of a deep connection between the mechanism of RNA splicing and small-RNA-mediated gene silencing, the presence of the Argonaute proteins and other small RNA components in the many species analysed strongly correlates with the number of introns in those species. Show less

Abstract A mutation within one allele of the p53 tumor suppressor gene can inactivate the
remaining wild-type allele in a dominant-negative manner and in some cases can exert an
additional oncogenic activity, known as mutant p53 'gain of function'(GOF). To study the role
of p53 mutations in prostate cancer and to discriminate between the dominant-negative
effect and the GOF activity of mutant p53, we measured, using microarrays, the expression
profiles of three immortalized… Show more

Abstract A mutation within one allele of the p53 tumor suppressor gene can inactivate the
remaining wild-type allele in a dominant-negative manner and in some cases can exert an
additional oncogenic activity, known as mutant p53 'gain of function'(GOF). To study the role
of p53 mutations in prostate cancer and to discriminate between the dominant-negative
effect and the GOF activity of mutant p53, we measured, using microarrays, the expression
profiles of three immortalized prostate epithelial cultures expressing wild-type, inactivated . Show less

Summary The most critical stage in initiation of melanoma metastasis is the radial to vertical
growth transition, yet the triggers of this transition remain elusive. We suggest that the
microenvironment drives melanoma metastasis independently of mutation acquisition. Here
we examined the changes in microenvironment that occur during melanoma radial growth.
We show that direct contact of melanoma cells with the remote epidermal layer triggers
vertical invasion via Notch… Show more

Summary The most critical stage in initiation of melanoma metastasis is the radial to vertical
growth transition, yet the triggers of this transition remain elusive. We suggest that the
microenvironment drives melanoma metastasis independently of mutation acquisition. Here
we examined the changes in microenvironment that occur during melanoma radial growth.
We show that direct contact of melanoma cells with the remote epidermal layer triggers
vertical invasion via Notch signaling activation, the latter serving to inhibit MITF function. .. Show less

The p53 gene is mutated in many human tumors. Cells of such tumors often contain
abundant mutant p53 (mutp53) protein, which may contribute actively to tumor progression
via a gain-of-function mechanism. We applied ChIP-on-chip analysis and identified the
vitamin D receptor (VDR) response element as overrepresented in promoter sequences
bound by mutp53. We report that mutp53 can interact functionally and physically with VDR.
Mutp53 is recruited to VDR-regulated genes and… Show more

The p53 gene is mutated in many human tumors. Cells of such tumors often contain
abundant mutant p53 (mutp53) protein, which may contribute actively to tumor progression
via a gain-of-function mechanism. We applied ChIP-on-chip analysis and identified the
vitamin D receptor (VDR) response element as overrepresented in promoter sequences
bound by mutp53. We report that mutp53 can interact functionally and physically with VDR.
Mutp53 is recruited to VDR-regulated genes and modulates their expression, augmenting ... Show less

Whole-genome mRNA expression data obtained during in-vitro cancerous transformation allowed us to decipherer key molecular events in tumorigenesis
We focused on a cluster of cell cycle genes that appear to derive the process and uncovered the transcriptional control of the genes in the cluster
We found promoter elements that couple the genes activity with the activity of two prime up-stream tumor suppressors, p53 and p21.
The transcription factors that control the cluster appear to… Show more

Whole-genome mRNA expression data obtained during in-vitro cancerous transformation allowed us to decipherer key molecular events in tumorigenesis
We focused on a cluster of cell cycle genes that appear to derive the process and uncovered the transcriptional control of the genes in the cluster
We found promoter elements that couple the genes activity with the activity of two prime up-stream tumor suppressors, p53 and p21.
The transcription factors that control the cluster appear to sum-up the activity of the two tumor suppressive channels and produce an expression level that is analogous to it. This expression pattern appears to determine proliferation rates, and potentially also, tumorigenesis.
Our findings provide for the first time a 3-way connection between gene expression, promoter architecture and activity of up-stream signaling pathways in mammalian cells. Show less