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1.
Nat Commun ; 14(1): 5466, 2023 09 25.
Artículo en Inglés | MEDLINE | ID: mdl-37749075

RESUMEN

The interplay between 3D chromatin architecture and gene silencing is incompletely understood. Here, we report a novel point mutation in the non-canonical SMC protein SMCHD1 that enhances its silencing capacity at endogenous developmental targets. Moreover, it also results in enhanced silencing at the facioscapulohumeral muscular dystrophy associated macrosatellite-array, D4Z4, resulting in enhanced repression of DUX4 encoded by this repeat. Heightened SMCHD1 silencing perturbs developmental Hox gene activation, causing a homeotic transformation in mice. Paradoxically, the mutant SMCHD1 appears to enhance insulation against other epigenetic regulators, including PRC2 and CTCF, while depleting long range chromatin interactions akin to what is observed in the absence of SMCHD1. These data suggest that SMCHD1's role in long range chromatin interactions is not directly linked to gene silencing or insulating the chromatin, refining the model for how the different levels of SMCHD1-mediated chromatin regulation interact to bring about gene silencing in normal development and disease.


Asunto(s)
Cromatina , Proteínas Cromosómicas no Histona , Distrofia Muscular Facioescapulohumeral , Animales , Ratones , Cromatina/genética , Epigenómica , Silenciador del Gen , Genes Homeobox , Distrofia Muscular Facioescapulohumeral/genética , Proteínas Cromosómicas no Histona/genética
2.
Epigenetics Chromatin ; 15(1): 26, 2022 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-35843975

RESUMEN

Embryonic development is dependent on the maternal supply of proteins through the oocyte, including factors setting up the adequate epigenetic patterning of the zygotic genome. We previously reported that one such factor is the epigenetic repressor SMCHD1, whose maternal supply controls autosomal imprinted expression in mouse preimplantation embryos and mid-gestation placenta. In mouse preimplantation embryos, X chromosome inactivation is also an imprinted process. Combining genomics and imaging, we show that maternal SMCHD1 is required not only for the imprinted expression of Xist in preimplantation embryos, but also for the efficient silencing of the inactive X in both the preimplantation embryo and mid-gestation placenta. These results expand the role of SMCHD1 in enforcing the silencing of Polycomb targets. The inability of zygotic SMCHD1 to fully restore imprinted X inactivation further points to maternal SMCHD1's role in setting up the appropriate chromatin environment during preimplantation development, a critical window of epigenetic remodelling.


Asunto(s)
Proteínas Cromosómicas no Histona , ARN Largo no Codificante , Inactivación del Cromosoma X , Animales , Blastocisto/fisiología , Cromatina/genética , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Desarrollo Embrionario , Impresión Genómica , Ratones , ARN Largo no Codificante/biosíntesis , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Cromosoma X
3.
Nat Commun ; 13(1): 1658, 2022 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-35351876

RESUMEN

The process of epigenetic silencing, while fundamentally important, is not yet completely understood. Here we report a replenishable female mouse embryonic stem cell (mESC) system, Xmas, that allows rapid assessment of X chromosome inactivation (XCI), the epigenetic silencing mechanism of one of the two X chromosomes that enables dosage compensation in female mammals. Through a targeted genetic screen in differentiating Xmas mESCs, we reveal that the BAF complex is required to create nucleosome-depleted regions at promoters on the inactive X chromosome during the earliest stages of establishment of XCI. Without this action gene silencing fails. Xmas mESCs provide a tractable model for screen-based approaches that enable the discovery of unknown facets of the female-specific process of XCI and epigenetic silencing more broadly.


Asunto(s)
ARN Largo no Codificante , Inactivación del Cromosoma X , Animales , Cromatina/genética , Compensación de Dosificación (Genética) , Epigénesis Genética , Femenino , Ratones , ARN Largo no Codificante/genética , Cromosoma X/genética , Inactivación del Cromosoma X/genética
4.
Elife ; 92020 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-33186096

RESUMEN

Genomic imprinting establishes parental allele-biased expression of a suite of mammalian genes based on parent-of-origin specific epigenetic marks. These marks are under the control of maternal effect proteins supplied in the oocyte. Here we report epigenetic repressor Smchd1 as a novel maternal effect gene that regulates the imprinted expression of ten genes in mice. We also found zygotic SMCHD1 had a dose-dependent effect on the imprinted expression of seven genes. Together, zygotic and maternal SMCHD1 regulate three classic imprinted clusters and eight other genes, including non-canonical imprinted genes. Interestingly, the loss of maternal SMCHD1 does not alter germline DNA methylation imprints pre-implantation or later in gestation. Instead, what appears to unite most imprinted genes sensitive to SMCHD1 is their reliance on polycomb-mediated methylation as germline or secondary imprints, therefore we propose that SMCHD1 acts downstream of polycomb imprints to mediate its function.


Asunto(s)
Proteínas Cromosómicas no Histona/metabolismo , Impresión Genómica/genética , Animales , Blastocisto , Proteínas Cromosómicas no Histona/genética , Metilación de ADN , Embrión de Mamíferos/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica/fisiología , Genotipo , Proteínas Fluorescentes Verdes , Masculino , Ratones , Células-Madre Neurales
5.
Sci Signal ; 13(636)2020 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-32546545

RESUMEN

Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) is an epigenetic regulator in which polymorphisms cause the human developmental disorder, Bosma arhinia micropthalmia syndrome, and the degenerative disease, facioscapulohumeral muscular dystrophy. SMCHD1 is considered a noncanonical SMC family member because its hinge domain is C-terminal, because it homodimerizes rather than heterodimerizes, and because SMCHD1 contains a GHKL-type, rather than an ABC-type ATPase domain at its N terminus. The hinge domain has been previously implicated in chromatin association; however, the underlying mechanism involved and the basis for SMCHD1 homodimerization are unclear. Here, we used x-ray crystallography to solve the three-dimensional structure of the Smchd1 hinge domain. Together with structure-guided mutagenesis, we defined structural features of the hinge domain that participated in homodimerization and nucleic acid binding, and we identified a functional hotspot required for chromatin localization in cells. This structure provides a template for interpreting the mechanism by which patient polymorphisms within the SMCHD1 hinge domain could compromise function and lead to facioscapulohumeral muscular dystrophy.


Asunto(s)
Proteínas Cromosómicas no Histona/química , Multimerización de Proteína , Animales , Proteínas Cromosómicas no Histona/genética , Cristalografía por Rayos X , Ratones , Ácidos Nucleicos/química , Ácidos Nucleicos/metabolismo , Dominios Proteicos , Estructura Cuaternaria de Proteína , Hermanos
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