RESUMO
Human skin tolerates a surprisingly high burden of oncogenic lesions. Although adult epidermis can suppress the expansion of individual mutant clones, the mechanisms behind tolerance to oncogene activation across broader regions of tissue are unclear. Here, we uncover a dynamic translational mechanism that coordinates oncogenic HRAS-induced hyperproliferation with loss of progenitor self-renewal to restrain aberrant growth and tumorigenesis. We identify translation initiator eIF2B5 as a central co-regulator of HRAS proliferation and cell fate choice. By coupling in vivo ribosome profiling with genetic screening, we provide direct evidence that oncogene-induced loss of progenitor self-renewal is driven by eIF2B5-mediated translation of ubiquitination genes. Ubiquitin ligase FBXO32 specifically inhibits epidermal renewal without affecting overall proliferation, thus restraining HRAS-driven tumorigenesis while maintaining normal tissue growth. Thus, oncogene-driven translation is not necessarily inherently tumor promoting but instead can manage widespread oncogenic stress by steering progenitor fate to prolong normal tissue growth.
Assuntos
Carcinogênese , Células Epidérmicas , Carcinogênese/genética , Diferenciação Celular , Proliferação de Células , Humanos , OncogenesRESUMO
In eukaryotic genomes, heterochromatin is targeted by RNAi machinery and/or by pathways requiring RNA elimination and transcription termination factors. However, a direct connection between termination machinery and RNA polymerase II (RNAPII) transcriptional activity at heterochromatic loci has remained elusive. Here, we show that, in fission yeast, the conserved cleavage and polyadenylation factor (CPF) is a key component involved in RNAi-independent assembly of constitutive and facultative heterochromatin domains and that CPF is broadly required to silence genes regulated by Clr4SUV39H. Remarkably, CPF is recruited to non-canonical termination sites within the body of genes by the YTH family RNA-binding protein Mmi1 and is required for RNAPII transcription termination and facultative heterochromatin assembly. CPF loading by Mmi1 also promotes the selective termination of long non-coding RNAs that regulate gene expression in cis. These analyses delineate a mechanism in which CPF loaded onto non-canonical termination sites specifies targets of heterochromatin assembly and gene silencing.
Assuntos
Inativação Gênica , Heterocromatina/metabolismo , RNA Polimerase II/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/genética , Terminação da Transcrição Genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Montagem e Desmontagem da Cromatina/genética , Exorribonucleases/genética , Exorribonucleases/metabolismo , Regulação Fúngica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Meiose/genética , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Interferência de RNA , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Fatores de Poliadenilação e Clivagem de mRNA/genéticaRESUMO
Iron metabolism is critical for sustaining life and maintaining human health. Here, we find that iron homeostasis is linked to facultative heterochromatin assembly and regulation of gene expression during adaptive genome control. We show that the fission yeast Clr4/Suv39h histone methyltransferase is part of a rheostat-like mechanism in which transcriptional upregulation of mRNAs in response to environmental change provides feedback to prevent their uncontrolled expression through heterochromatin assembly. Interestingly, proper iron homeostasis is required, as iron depletion or downregulation of iron transporters causes defects in heterochromatin assembly and unrestrained upregulation of gene expression. Remarkably, an unbiased genetic screen revealed that restoration of iron homeostasis is sufficient to re-establish facultative heterochromatin and proper gene control genome-wide. These results establish a role for iron homeostasis in facultative heterochromatin assembly and reveal a dynamic mechanism for reprogramming the genome in response to environmental changes.