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1.
Nature ; 628(8006): 122-129, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38448590

RESUMEN

Genomic imprinting-the non-equivalence of maternal and paternal genomes-is a critical process that has evolved independently in many plant and mammalian species1,2. According to kinship theory, imprinting is the inevitable consequence of conflictive selective forces acting on differentially expressed parental alleles3,4. Yet, how these epigenetic differences evolve in the first place is poorly understood3,5,6. Here we report the identification and molecular dissection of a parent-of-origin effect on gene expression that might help to clarify this fundamental question. Toxin-antidote elements (TAs) are selfish elements that spread in populations by poisoning non-carrier individuals7-9. In reciprocal crosses between two Caenorhabditis tropicalis wild isolates, we found that the slow-1/grow-1 TA is specifically inactive when paternally inherited. This parent-of-origin effect stems from transcriptional repression of the slow-1 toxin by the PIWI-interacting RNA (piRNA) host defence pathway. The repression requires PIWI Argonaute and SET-32 histone methyltransferase activities and is transgenerationally inherited via small RNAs. Remarkably, when slow-1/grow-1 is maternally inherited, slow-1 repression is halted by a translation-independent role of its maternal mRNA. That is, slow-1 transcripts loaded into eggs-but not SLOW-1 protein-are necessary and sufficient to counteract piRNA-mediated repression. Our findings show that parent-of-origin effects can evolve by co-option of the piRNA pathway and hinder the spread of selfish genes that require sex for their propagation.


Asunto(s)
Caenorhabditis , Impresión Genómica , ARN de Interacción con Piwi , Secuencias Repetitivas de Ácidos Nucleicos , Animales , Femenino , Masculino , Alelos , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Caenorhabditis/genética , Caenorhabditis/metabolismo , Cruzamientos Genéticos , Padre , Genoma/genética , Impresión Genómica/genética , Organismos Hermafroditas/genética , Histona Metiltransferasas/genética , Histona Metiltransferasas/metabolismo , Madres , Oocitos/metabolismo , ARN de Interacción con Piwi/genética , Biosíntesis de Proteínas , Secuencias Repetitivas de Ácidos Nucleicos/genética , ARN Mensajero/genética , Toxinas Biológicas/genética , Transcripción Genética
2.
Nat Methods ; 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38969721

RESUMEN

The systematic determination of protein function is a key goal of modern biology, but remains challenging with current approaches. Here we present ORFtag, a versatile, cost-effective and highly efficient method for the massively parallel tagging and functional interrogation of proteins at the proteome scale. ORFtag uses retroviral vectors bearing a promoter, peptide tag and splice donor to generate fusions between the tag and endogenous open reading frames (ORFs). We demonstrate the utility of ORFtag through functional screens for transcriptional activators, repressors and posttranscriptional regulators in mouse embryonic stem cells. Each screen recovers known and identifies new regulators, including long ORFs inaccessible by other methods. Among other hits, we find that Zfp574 is a highly selective transcriptional activator and that oncogenic fusions often function as transactivators.

3.
Elife ; 132024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38995818

RESUMEN

Members of the diverse heterochromatin protein 1 (HP1) family play crucial roles in heterochromatin formation and maintenance. Despite the similar affinities of their chromodomains for di- and tri-methylated histone H3 lysine 9 (H3K9me2/3), different HP1 proteins exhibit distinct chromatin-binding patterns, likely due to interactions with various specificity factors. Previously, we showed that the chromatin-binding pattern of the HP1 protein Rhino, a crucial factor of the Drosophila PIWI-interacting RNA (piRNA) pathway, is largely defined by a DNA sequence-specific C2H2 zinc finger protein named Kipferl (Baumgartner et al., 2022). Here, we elucidate the molecular basis of the interaction between Rhino and its guidance factor Kipferl. Through phylogenetic analyses, structure prediction, and in vivo genetics, we identify a single amino acid change within Rhino's chromodomain, G31D, that does not affect H3K9me2/3 binding but disrupts the interaction between Rhino and Kipferl. Flies carrying the rhinoG31D mutation phenocopy kipferl mutant flies, with Rhino redistributing from piRNA clusters to satellite repeats, causing pronounced changes in the ovarian piRNA profile of rhinoG31D flies. Thus, Rhino's chromodomain functions as a dual-specificity module, facilitating interactions with both a histone mark and a DNA-binding protein.


Asunto(s)
Cromatina , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona , Proteínas de Drosophila , Drosophila melanogaster , Animales , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Cromatina/metabolismo , Cromatina/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Evolución Molecular , Filogenia , Unión Proteica , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/genética , Histonas/metabolismo , Histonas/genética , ADN/metabolismo , ADN/genética
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