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SETDB1 compacts the inactive X chromosome in part through silencing an enhancer in the IL1RAPL1 gene

ABSTRACT: The product of dosage compensation in human females is the compacted inactive X chromosome (Xi). Here we show that loss of SET domain bifurcated 1 (SETDB1) results in decompaction of the Xi territory coupled with reactivation on the Xi of a powerful enhancer within the 1.4 Mb interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene at Xp21.2. The enhancer is centrally located in a 0.5 Mb region corresponding to the 3’ third of the IL1RAPL1 locus that transitions from a heterochromatic territory to a euchromatic configuration on the Xi in the absence of SETDB1. This same region showing chromatin instability is part of a common chromosome fragile site that is frequently deleted or rearranged in patients afflicted with intellectual disability and other neurological ailments. Immediately adjacent to the enhancer is an ERVL-MaLR element that drives bi-directional transcription of novel long sense and antisense transcripts. Deletion of the enhancer from the Xa (but not Xi), resulted in detection of bi-directional expression from the Xi coupled with decompaction of the chromosome territory, supporting a critical role for SETDB1 in maintaining this interval in a silent state to facilitate Xi compaction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113399 | GEO | 2018/11/14

REPOSITORIES: GEO

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Cell fusion-mediated pluripotent reprogramming triggers ordered changes in chromatin and gene expression across the human inactive X chromosome

Project description:Erasure of epigenetic memory is required to convert somatic cells towards pluripotency. Reactivation of the inactive X chromosome (Xi) has been used to model epigenetic reprogramming in mouse, but human studies are hampered by Xi epigenetic instability and difficulties in tracking partially reprogrammed iPSCs. Here we used cell fusion to examine the earliest events in the reprogramming-induced Xi reactivation of human female fibroblasts. We show a rapid and widespread loss of Xi-associated H3K27me3 and XIST in fused cells that precedes the bi-allelic expression of selected Xi-genes by many heterokaryons (30-50%). After cell division, RNA-FISH and RNA-Seq analysis confirmed that Xi reactivation remained partial and showed that induction of human pluripotency-specific XACT transcripts occurred, but was rare (1%). These data effectively separate pre- and post-mitotic events in reprogramming-induced Xi reactivation, and suggest a hierarchy where early events such as XIST-delocalisation, are required but are insufficient to establish stable human X reactivation. We performed RNA-sequencing of human fibroblast clones derived from TERT-immortalised NHDF17914 (Lonza) before and at 5 days after fusion with mouse ESC (E14Tg2a:puroR). Two biological replicates were performed and sequenced.

2016-07-01 | E-GEOD-77443 | biostudies-arrayexpress

Cell fusion-mediated pluripotent reprogramming triggers ordered changes in chromatin and gene expression across the human inactive X chromosome

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An Xist-dependent protein assembly mediates Xist localization and gene silencing

Project description:Nuclear compartments play diverse roles in regulating gene expression, yet the molecular forces and components driving compartment formation are not well understood. Studying how the lncRNA Xist establishes the inactive-X-chromosome (Xi)-compartment, we found that the Xist RNA-binding-proteins PTBP1, MATR3, TDP43, and CELF1 form a condensate to create an Xi-domain that can be sustained in the absence of Xist. The E-repeat-sequence of Xist serves a multivalent binding-platform for these proteins. Without the E-repeat, Xist initially coats the X-chromosome during XCI onset but subsequently disperses across the nucleus with loss of gene silencing. Recruitment of PTBP1, MATR3, TDP-43 or CELF1 to E-Xist rescues these phenotypes, and requires both self-association of MATR3 and TDP-43 and a heterotypic PTBP1-MATR3-interaction. Together, our data reveal that Xist sequesters itself within the Xi-territory and perpetuates gene silencing by seeding a protein-condensate. Our findings uncover an unanticipated mechanism for epigenetic memory and elucidate the interplay between RNA and RNA-binding-proteins in creating compartments for gene regulation.

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c-Myc/BMI1 axis is essential for SETDB1-mediated breast tumorigenesis

Project description:Copy number gain/amplification of SETDB1 has been found in several human cancers, but the detailed oncogenic mechanism(s) of SETDB1 contributing to breast cancer remains largely unexplored. In this project, we analyzed the transcriptome of human breast cancer cell lines (MDA-MB-231 and MDA-MB-453) upon silencing of SETDB1 to explore the potential mechanism(s) underlying SETDB1 promoted breast cancer. In MDA-MB-231 cells, SETDB1 was silenced by shRNA-1. In MDA-MB-453 cells, SETDB1 was reduced by shRNA-3.

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Site-specific silencing of regulatory elements as a mechanism of X-inactivation

Project description:The inactive X chromosome’s (Xi) physical territory is microscopically devoid of transcriptional hallmarks and enriched in silencing-associated modifications. How these microscopic signatures relate to specific Xi sequence is unknown. This study reports the profiling of Xi gene expression and chromatin states at high-resolution via allele-specific sequencing in F1 hybrid mouse trophoblast stem cells (TSCs). Datasets provided include those generated from strand-specific RNA-Seq, ChIP-Seq, FAIRE-Seq, and DNase-Seq protocols. Included for each dataset are FASTQ files, BED alignments and WIG files with coordinates relative to UCSC genome build mm9, and _snp files that report the location of all SNP-overlapping reads. The F1 TSC lines profiled were generated from crosses between CAST/EiJ (Cast) and C57BL/6J (B6) mice. C/B denotes a Cast mother and B6 father, and B/C denotes a B6 mother and Cast father.

2012-11-21 | E-GEOD-39406 | biostudies-arrayexpress

Human naïve pluripotent stem cells exhibit X chromosome dampening and X-inactivation (RRBS)

Project description:Naïve human embryonic stem cells (hESCs) can be derived from primed hESCs or directly from blastocysts, but their X-chromosome state has remained unresolved. We found that the inactive X-chromosome (Xi) of primed hESCs was reactivated in naïve culture conditions. Similar to cells of the blastocyst, resulting naive cells exhibited two active X-chromosomes with XIST expression and chromosome-wide transcriptional dampening, and initiated XIST-mediated X-inactivation upon differentiation. Both establishment and exit from the naïve state (differentiation) happened via an XIST-negative XaXa intermediate. Together, these findings identify a cell culture system for functionally exploring the two X-chromosome dosage compensation processes in early human development: X-dampening and X-inactivation. Furthermore, the naïve state reset Xi abnormalities of primed hESCs, providing cells better suited for downstream applications. However, naïve hESCs displayed differences to the embryo because XIST expression was predominantly mono-allelic instead of bi-allelic, and X-inactivation was non-random, indicating the need for further culture improvement.

2016-10-21 | GSE87235 | GEO

Human naïve pluripotent stem cells exhibit X chromosome dampening and X-inactivation (single cell RNA-Seq)

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Human naïve pluripotent stem cells exhibit X chromosome dampening and X-inactivation (RNA-Seq)

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Site-specific silencing of regulatory elements as a mechanism of X-inactivation

2012-11-21 | GSE39406 | GEO

Timecourse gene expression microarray analysis of bi-allelic targeted Setdb1 mutant mouse ES cells, comparing cells with one inducible conditional (floxed) null allele and a second constitutive null allele, to control mouse ES cell lines.

Project description:Gene expression microarray analysis of Setdb1 inducible conditional (floxed) mutant (Setdb1^tm1c(EUCOMM)Wtsi/Setdb1^tm1Wcs) compared to control (Setdb1^tm1c(EUCOMM)Wtsi/+) ES cell lines, without 4'OHT treatment, and timecourse samples following a 48 hour 4'OHT treatment. The 4'OHT induces Cre recombination via the Rosa26CreERT2 knock-in system, to convert the tm1c conditional allele to the tm1d null allele. The Setdb1^tm1Wcs allele is a constitutive null allele. Experimental and control Setdb1 ES cells were each treated with 4’OHT for 48 hours, and gene expression was analyzed at days 0 (before treatment), 2 (end of treatment period), 3, 4, and 6 days. Three biological replicates per genotype per timepoint (individual ES clones) were performed. Parental ES cell lines are from the International Knockout Mouse Consortium (IKMC - EUCOMM and KOMP-CSD programmes) and were modified using bi-allelic gene targeting with a targeted trapping vector generated by re-purposing Intermediate Vectors from the IKMC resource.

2017-09-12 | E-MTAB-5931 | biostudies-arrayexpress

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