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1.
Mol Syst Biol ; 17(5): e10138, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-34042294

RESUMEN

The consequence of a mutation can be influenced by the context in which it operates. For example, loss of gene function may be tolerated in one genetic background, and lethal in another. The extent to which mutant phenotypes are malleable, the architecture of modifiers and the identities of causal genes remain largely unknown. Here, we measure the fitness effects of ~ 1,100 temperature-sensitive alleles of yeast essential genes in the context of variation from ten different natural genetic backgrounds and map the modifiers for 19 combinations. Altogether, fitness defects for 149 of the 580 tested genes (26%) could be suppressed by genetic variation in at least one yeast strain. Suppression was generally driven by gain-of-function of a single, strong modifier gene, and involved both genes encoding complex or pathway partners suppressing specific temperature-sensitive alleles, as well as general modifiers altering the effect of many alleles. The emerging frequency of suppression and range of possible mechanisms suggest that a substantial fraction of monogenic diseases could be managed by modulating other gene products.


Asunto(s)
Mutación con Ganancia de Función , Genes Esenciales , Saccharomyces cerevisiae/crecimiento & desarrollo , Regulación Fúngica de la Expresión Génica , Genes Modificadores , Variación Genética , Mutación , Fenotipo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética
2.
Mol Syst Biol ; 16(9): e9828, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32939983

RESUMEN

Essential genes tend to be highly conserved across eukaryotes, but, in some cases, their critical roles can be bypassed through genetic rewiring. From a systematic analysis of 728 different essential yeast genes, we discovered that 124 (17%) were dispensable essential genes. Through whole-genome sequencing and detailed genetic analysis, we investigated the genetic interactions and genome alterations underlying bypass suppression. Dispensable essential genes often had paralogs, were enriched for genes encoding membrane-associated proteins, and were depleted for members of protein complexes. Functionally related genes frequently drove the bypass suppression interactions. These gene properties were predictive of essential gene dispensability and of specific suppressors among hundreds of genes on aneuploid chromosomes. Our findings identify yeast's core essential gene set and reveal that the properties of dispensable essential genes are conserved from yeast to human cells, correlating with human genes that display cell line-specific essentiality in the Cancer Dependency Map (DepMap) project.


Asunto(s)
Genes Esenciales , Genes Fúngicos , Saccharomyces cerevisiae/genética , Supresión Genética , Aneuploidia , Evolución Molecular , Eliminación de Gen , Duplicación de Gen , Redes Reguladoras de Genes , Genes Supresores , Complejos Multiproteicos/metabolismo
3.
Genome Res ; 25(12): 1848-59, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26486724

RESUMEN

Mammalian gene expression displays widespread circadian oscillations. Rhythmic transcription underlies the core clock mechanism, but it cannot explain numerous observations made at the level of protein rhythmicity. We have used ribosome profiling in mouse liver to measure the translation of mRNAs into protein around the clock and at high temporal and nucleotide resolution. We discovered, transcriptome-wide, extensive rhythms in ribosome occupancy and identified a core set of approximately 150 mRNAs subject to particularly robust daily changes in translation efficiency. Cycling proteins produced from nonoscillating transcripts revealed thus-far-unknown rhythmic regulation associated with specific pathways (notably in iron metabolism, through the rhythmic translation of transcripts containing iron responsive elements), and indicated feedback to the rhythmic transcriptome through novel rhythmic transcription factors. Moreover, estimates of relative levels of core clock protein biosynthesis that we deduced from the data explained known features of the circadian clock better than did mRNA expression alone. Finally, we identified uORF translation as a novel regulatory mechanism within the clock circuitry. Consistent with the occurrence of translated uORFs in several core clock transcripts, loss-of-function of Denr, a known regulator of reinitiation after uORF usage and of ribosome recycling, led to circadian period shortening in cells. In summary, our data offer a framework for understanding the dynamics of translational regulation, circadian gene expression, and metabolic control in a solid mammalian organ.


Asunto(s)
Relojes Circadianos/genética , Ritmo Circadiano/genética , Perfilación de la Expresión Génica , Hígado/metabolismo , Sistemas de Lectura Abierta , Ribosomas/genética , Ribosomas/metabolismo , Transcriptoma , Regiones no Traducidas 5' , Animales , Biomarcadores , Biología Computacional/métodos , Regulación de la Expresión Génica , Ontología de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Masculino , Ratones , Biosíntesis de Proteínas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Elementos de Respuesta
4.
PLoS One ; 15(1): e0224646, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31905202

RESUMEN

Twelve human THAP proteins share the THAP domain, an evolutionary conserved zinc-finger DNA-binding domain. Studies of different THAP proteins have indicated roles in gene transcription, cell proliferation and development. We have analyzed this protein family, focusing on THAP7 and THAP11. We show that human THAP proteins possess differing homo- and heterodimer formation properties and interaction abilities with the transcriptional co-regulator HCF-1. HEK-293 cells lacking THAP7 were viable but proliferated more slowly. In contrast, HEK-293 cells were very sensitive to THAP11 alteration. Nevertheless, HEK-293 cells bearing a THAP11 mutation identified in a patient suffering from cobalamin disorder (THAP11F80L) were viable although proliferated more slowly. Cobalamin disorder is an inborn vitamin deficiency characterized by neurodevelopmental abnormalities, most often owing to biallelic mutations in the MMACHC gene, whose gene product MMACHC is a key enzyme in the cobalamin (vitamin B12) metabolic pathway. We show that THAP11F80L selectively affected promoter binding by THAP11, having more deleterious effects on a subset of THAP11 targets, and resulting in altered patterns of gene expression. In particular, THAP11F80L exhibited a strong effect on association with the MMACHC promoter and led to a decrease in MMACHC gene transcription, suggesting that the THAP11F80L mutation is directly responsible for the observed cobalamin disorder.


Asunto(s)
Oxidorreductasas/genética , Proteínas Represoras/genética , Deficiencia de Vitamina B 12/genética , Vitamina B 12/genética , Línea Celular , Proliferación Celular/genética , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica/genética , Células HEK293 , Factor C1 de la Célula Huésped/genética , Humanos , Redes y Vías Metabólicas/genética , Mutación/genética , Regiones Promotoras Genéticas , Unión Proteica/genética , Vitamina B 12/metabolismo , Deficiencia de Vitamina B 12/metabolismo , Deficiencia de Vitamina B 12/patología
5.
Mol Cell Biol ; 39(5)2019 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-30559308

RESUMEN

Host-cell factor 1 (HCF-1), encoded by the ubiquitously expressed X-linked gene Hcfc1, is an epigenetic coregulator important for mouse development and cell proliferation, including during liver regeneration. We used a hepatocyte-specific inducible Hcfc1 knock-out allele (called Hcfc1hepKO), to induce HCF-1 loss in hepatocytes of hemizygous Hcfc1hepKO/Y males by four days. In heterozygous Hcfc1hepKO/+ females, owing to random X-chromosome inactivation, upon Hcfc1hepKO allele induction, a 50/50 mix of HCF-1 positive and negative hepatocyte clusters is engineered. The livers with Hcfc1hepKO/Y hepatocytes displayed a 21-24-day terminal non-alcoholic fatty liver (NAFL) followed by non-alcoholic steatohepatitis (NASH) disease progression typical of severe NAFL disease (NAFLD). In contrast, in livers with heterozygous Hcfc1hepKO/+ hepatocytes, HCF-1-positive hepatocytes replaced HCF-1-negative hepatocytes and revealed only mild-NAFL development. Loss of HCF-1 led to loss of PGC1α protein, probably owing to its destabilization, and deregulation of gene expression particularly of genes involved in mitochondrial structure and function, likely explaining the severe Hcfc1 hepKO/Y liver pathology. Thus, HCF-1 is essential for hepatocyte function, likely playing both transcriptional and non-transcriptional roles. These genetically-engineered loss-of-HCF-1 mice can be used to study NASH as well as NAFLD resolution.


Asunto(s)
Factor C1 de la Célula Huésped/genética , Proteína de Factor 1 del Huésped/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Alelos , Animales , Proliferación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Genes Ligados a X , Hepatocitos/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/genética
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