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SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE174113 | GEO | 2021/05/10

REPOSITORIES: GEO

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SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease.

Project description: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.

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SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease

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Relating SMCHD1 structure to its function in epigenetic silencing.

Project description:The structural maintenance of chromosomes hinge domain containing protein 1 (SMCHD1) is a large multidomain protein involved in epigenetic gene silencing. Variations in the SMCHD1 gene are associated with two debilitating human disorders, facioscapulohumeral muscular dystrophy (FSHD) and Bosma arhinia microphthalmia syndrome (BAMS). Failure of SMCHD1 to silence the D4Z4 macro-repeat array causes FSHD, yet the consequences on gene silencing of SMCHD1 variations associated with BAMS are currently unknown. Despite the interest due to these roles, our understanding of the SMCHD1 protein is in its infancy. Most knowledge of SMCHD1 function is based on its similarity to the structural maintenance of chromosomes (SMC) proteins, such as cohesin and condensin. SMC proteins and SMCHD1 share similar domain organisation and affect chromatin conformation. However, there are important differences between the domain architectures of SMC proteins and SMCHD1, which distinguish SMCHD1 as a non-canonical member of the family. In the last year, the crystal structures of the two key domains crucial to SMCHD1 function, the ATPase and hinge domains, have emerged. These structures reveal new insights into how SMCHD1 may bind and regulate chromatin structure, and address how amino acid variations in SMCHD1 may contribute to BAMS and FSHD. Here, we contrast SMCHD1 with canonical SMC proteins, and relate the ATPase and hinge domain structures to their roles in SMCHD1-mediated epigenetic silencing and disease.

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Exploring the Roles of RNAs in Chromatin Architecture Using Deep Learning.

Project description:Recent studies have highlighted the impact of both transcription and transcripts on 3D genome organization, particularly its dynamics. Here, we propose a deep learning framework, called AkitaR, that leverages both genome sequences and genome-wide RNA-DNA interactions to investigate the roles of chromatin-associated RNAs (caRNAs) on genome folding in HFFc6 cells. In order to disentangle the cis- and trans-regulatory roles of caRNAs, we compared models with nascent transcripts, trans-located caRNAs, open chromatin data, or DNA sequence alone. Both nascent transcripts and trans-located caRNAs improved the models' predictions, especially at cell-type-specific genomic regions. Analyses of feature importance scores revealed the contribution of caRNAs at TAD boundaries, chromatin loops and nuclear sub-structures such as nuclear speckles and nucleoli to the models' predictions. Furthermore, we identified non-coding RNAs (ncRNAs) known to regulate chromatin structures, such as MALAT1 and NEAT1, as well as several novel RNAs, RNY5, RPPH1, POLG-DT and THBS1-IT, that might modulate chromatin architecture through trans-interactions in HFFc6. Our modeling also suggests that transcripts from Alus and other repetitive elements may facilitate chromatin interactions through trans R-loop formation. Our findings provide new insights and generate testable hypotheses about the roles of caRNAs in shaping chromatin organization.

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Exploring the roles of RNAs in chromatin architecture using deep learning.

Project description:Recent studies have highlighted the impact of both transcription and transcripts on 3D genome organization, particularly its dynamics. Here, we propose a deep learning framework, called AkitaR, that leverages both genome sequences and genome-wide RNA-DNA interactions to investigate the roles of chromatin-associated RNAs (caRNAs) on genome folding in HFFc6 cells. In order to disentangle the cis- and trans-regulatory roles of caRNAs, we have compared models with nascent transcripts, trans-located caRNAs, open chromatin data, or DNA sequence alone. Both nascent transcripts and trans-located caRNAs improve the models' predictions, especially at cell-type-specific genomic regions. Analyses of feature importance scores reveal the contribution of caRNAs at TAD boundaries, chromatin loops and nuclear sub-structures such as nuclear speckles and nucleoli to the models' predictions. Furthermore, we identify non-coding RNAs (ncRNAs) known to regulate chromatin structures, such as MALAT1 and NEAT1, as well as several new RNAs, RNY5, RPPH1, POLG-DT and THBS1-IT1, that might modulate chromatin architecture through trans-interactions in HFFc6. Our modeling also suggests that transcripts from Alus and other repetitive elements may facilitate chromatin interactions through trans R-loop formation. Our findings provide insights and generate testable hypotheses about the roles of caRNAs in shaping chromatin organization.

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Silencing at Drosophila telomeres: nuclear organization and chromatin structure play critical roles.

Project description:Transgenes inserted into the telomeric regions of Drosophila melanogaster chromosomes exhibit position effect variegation (PEV), a mosaic silencing characteristic of euchromatic genes brought into juxtaposition with heterochromatin. Telomeric transgenes on the second and third chromosomes are flanked by telomeric associated sequences (TAS), while fourth chromosome telomeric transgenes are most often associated with repetitious transposable elements. Telomeric PEV on the second and third chromosomes is suppressed by mutations in Su(z)2, but not by mutations in Su(var)2-5 (encoding HP1), while the converse is true for telomeric PEV on the fourth chromosome. This genetic distinction allowed for a spatial and molecular analysis of telomeric PEV. Reciprocal translocations between the fourth chromosome telomeric region containing a transgene and a second chromosome telomeric region result in a change in nuclear location of the transgene. While the variegating phenotype of the white transgene is suppressed, sensitivity to a mutation in HP1 is retained. Corresponding changes in the chromatin structure and inducible activity of an associated hsp26 transgene are observed. The data indicate that both nuclear organization and local chromatin structure play a role in this telomeric PEV.

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