Perturbed maintenance of transcriptional repression on the inactive X-chromosome in the mouse brain after Xist deletion

Adrianse, Robin L.; Smith, Kaleb; Gatbonton-Schwager, Tonibelle; Sripathy, Smitha; Lao, Uyen; Foss, Eric J.; Boers, Ruben; Boers, Joachim; Gribnau, Joost; Bedalov, Antonio

doi:10.1186/s13072-018-0219-8

Cited by 41 publications

(51 citation statements)

References 33 publications

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“…There was also overlap between the regions of XIST required for H3K27me3 and MacroH2A recruitment, and inhibition with GSK343 substantially reduced the recruitment of both to the XIST-coated domain, indicating that MacroH2A recruitment was dependent upon the catalytic activity of PRC2. The discovery of this novel association has yet to be investigated in mouse models, though both have been observed to be lost when Xist is deleted (43,44). At time of writing the mechanisms underlying the connection between PRC2 and MacroH2A during XCI are unknown.…”

Section: Discussionmentioning

confidence: 99%

Independent recruitment of PRC1 and PRC2 by human XIST

Dixon-McDougall

Brown

2020

Preprint

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XIST establishes inactivation across its chromosome of origin, even when expressed from autosomal transgenes. To identify the regions of human XIST essential for recruiting heterochromatic marks we generated a series of overlapping deletions in an autosomal inducible XIST transgene. We examined the ability of each construct to enrich its unified XIST territory with the histone marks established by PRC1 and PRC2 as well as the heterochromatin factors MacroH2A and SMCHD1. PRC1 recruitment required four distinct regions of XIST, and these were completely distinct from the two domains crucial for PRC2 recruitment. Both the domains required and the impact of inhibitors suggest that PRC1 is required for SMCHD1 while PRC2 function is necessary for MacroH2A recruitment, although incomplete overlap of regions implicates a role for additional factors. The independence of the PRC1/PRC2 pathways, yet important of all regions tested, demonstrate both modularity and cooperativity across the XIST lncRNA.Author SummaryXIST functions as a long, non-protein coding, RNA to initiate various pathways for the silencing of one of the two X chromosomes in female placental mammals. CRISPR-directed mutations of an inducible human XIST construct in somatic cells allowed us to discover which regions of the RNA are required for chromatin modification and protein recruitment. This was the first large-scale dissection of human XIST domains, and every function assessed was dependent on multiple regions of XIST, suggesting considerable interactions between domains of XIST. We observed similarities, but also differences, with the domains previously identified in mouse Xist and demonstrated the presence of independent pathways for chromosome reorganization in humans as well as ascribing new functionality to regions of XIST. The ability of XIST to inactivate large sections of chromosomes from which it is expressed makes it both an exciting potential therapeutic for chromosome number abnormalities as well as a paradigm for how non-coding RNA genes are able to regulate cellular biology.

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Section: Discussionmentioning

confidence: 99%

Independent recruitment of PRC1 and PRC2 by human XIST

Dixon-McDougall

Brown

2020

Preprint

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“…Studies on maintenance of XCI have revealed several principles by which gene silencing is maintained. The factors and mechanisms that have been involved in maintenance of XCI include Xist [ 45 , 60 , 83 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ], DNA methylation [ 83 , 84 , 85 , 88 , 102 , 103 ], histone deacetylation [ 83 ], Polycomb [ 104 , 105 ], H3K9me3 [ 106 ] and macroH2A [ 70 , 107 , 108 ], and likely include additional layers of regulation as well.…”

Section: Maintenance Of XCImentioning

confidence: 99%

“…Erosion of XCI in somatic cells may not manifest itself after several weeks in culture, but could be relevant in aging, although XCR in aging remains largely unclear [ 113 ]. Fourth, several studies have reported examples of partial gene-specific loss of maintenance of XCI upon Xist deletion in the soma [ 97 , 99 ]. Such examples include interesting observations in the immune system where Xist and heterochromatin modifications can show altered patterns in mature naive T and B cells [ 114 , 115 ].…”

Section: Maintenance Of XCImentioning

confidence: 99%

New Insights into X-Chromosome Reactivation during Reprogramming to Pluripotency

Panda

Ż̷ylicz

Pasque

2020

Cells

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Dosage compensation between the sexes results in one X chromosome being inactivated during female mammalian development. Chromosome-wide transcriptional silencing from the inactive X chromosome (Xi) in mammalian cells is erased in a process termed X-chromosome reactivation (XCR), which has emerged as a paradigm for studying the reversal of chromatin silencing. XCR is linked with germline development and induction of naive pluripotency in the epiblast, and also takes place upon reprogramming somatic cells to induced pluripotency. XCR depends on silencing of the long non-coding RNA (lncRNA) X inactive specific transcript (Xist) and is linked with the erasure of chromatin silencing. Over the past years, the advent of transcriptomics and epigenomics has provided new insights into the transcriptional and chromatin dynamics with which XCR takes place. However, multiple questions remain unanswered about how chromatin and transcription related processes enable XCR. Here, we review recent work on establishing the transcriptional and chromatin kinetics of XCR, as well as discuss a model by which transcription factors mediate XCR not only via Xist repression, but also by direct targeting of X-linked genes.

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“…We used an epigenetic marker of the inactive X-chromosome, the Histone H3 trimethyl-lysine 27 (H3K27me3) modification, which co-localizes with Xist RNA [39]. The antibody used was rabbit anti-tri-methyl-histone H3 K27-3 m (1:1000, Cell Signaling catalogue #9733S), which has been previously validated and used in mice under similar immunofluorescence conditions [39,102]. The secondary fluorescently labeled antibody was Alexa Fluor 568-conjugated goat anti-rabbit (1:1000; Life Technologies catalogue #A11011).…”

Section: Immunofluorescence and Microscopymentioning

confidence: 99%

Wild mice with different social network sizes vary in brain gene expression

Lopes

König

2020

BMC Genomics

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Background: Appropriate social interactions influence animal fitness by impacting several processes, such as mating, territory defense, and offspring care. Many studies shedding light on the neurobiological underpinnings of social behavior have focused on nonapeptides (vasopressin, oxytocin, and homologues) and on sexual or parentoffspring interactions. Furthermore, animals have been studied under artificial laboratory conditions, where the consequences of behavioral responses may not be as critical as when expressed under natural environments, therefore obscuring certain physiological responses. We used automated recording of social interactions of wild house mice outside of the breeding season to detect individuals at both tails of a distribution of egocentric network sizes (characterized by number of different partners encountered per day). We then used RNA-seq to perform an unbiased assessment of neural differences in gene expression in the prefrontal cortex, the hippocampus and the hypothalamus between these mice with naturally occurring extreme differences in social network size. Results: We found that the neurogenomic pathways associated with having extreme social network sizes differed between the sexes. In females, hundreds of genes were differentially expressed between animals with small and large social network sizes, whereas in males very few were. In males, X-chromosome inactivation pathways in the prefrontal cortex were the ones that better differentiated animals with small from those with large social network sizes animals. In females, animals with small network size showed up-regulation of dopaminergic production and transport pathways in the hypothalamus. Additionally, in females, extracellular matrix deposition on hippocampal neurons was higher in individuals with small relative to large social network size. Conclusions: Studying neural substrates of natural variation in social behavior in traditional model organisms in their habitat can open new targets of research for understanding variation in social behavior in other taxa.

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Perturbed maintenance of transcriptional repression on the inactive X-chromosome in the mouse brain after Xist deletion

Cited by 41 publications

References 33 publications

Independent recruitment of PRC1 and PRC2 by human XIST

Independent recruitment of PRC1 and PRC2 by human XIST

New Insights into X-Chromosome Reactivation during Reprogramming to Pluripotency

Wild mice with different social network sizes vary in brain gene expression

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