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Retroelements and DUX4 Create Primate-specific Promoters for Germline Genes

ABSTRACT: The human double-homeodomain retrogene DUX4 is normally expressed at high levels in germ cells of the testis. When aberrantly expressed in muscle its protein product causes facioscapulohumeral muscular dystrophy (FSHD), perhaps partly by inducing inappropriate expression of germline genes. DUX4 can bind >60,000 locations in the human genome that contain a strongly enriched sequence motif. Numerous long terminal repeat (LTR) class repetitive elements are enriched among DUX4 binding sites, including many from the mammalian apparent LTR-retrotransposon (MaLR) family as well as some ERVL and ERVK types, with MaLRs comprising ~1/3 of DUX4’s binding sites. We performed RNA-seq on myoblasts over-expressing DUX4 and find that DUX4 binding activates transcription of some but not all bound repeat types. Some of these activated repetitive elements comprise novel promoters for genes, long non-coding RNAs and antisense transcripts. We show that some of these chimeric repeat-initiated transcripts are expressed in testis and FSHD patient myotubes. The acquisition of MaLR-LTR elements during mammalian evolution may therefore have allowed rewiring of the transcriptional network. We also find that the pericentromeric satellite HSATII can be bound by DUX4 and that its transcription is massively induced by DUX4 over-expression. Our findings suggest a role for repetitive element transcripts in muscle disease and in the biology of normal testis. RNA-seq of two myoblast cell lines transduced with lentivirus carrying DUX4, and two control myoblast lines

ORGANISM(S): Homo sapiens

SUBMITTER: Zizhen yao

PROVIDER: E-GEOD-45883 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis.

Project description:The human double-homeodomain retrogene DUX4 is expressed in the testis and epigenetically repressed in somatic tissues. Facioscapulohumeral muscular dystrophy (FSHD) is caused by mutations that decrease the epigenetic repression of DUX4 in somatic tissues and result in mis-expression of this transcription factor in skeletal muscle. DUX4 binds sites in the human genome that contain a double-homeobox sequence motif, including sites in unique regions of the genome as well as many sites in repetitive elements. Using ChIP-seq and RNA-seq on myoblasts transduced with DUX4 we show that DUX4 binds and activates transcription of mammalian apparent LTR-retrotransposons (MaLRs), endogenous retrovirus (ERVL and ERVK) elements, and pericentromeric satellite HSATII sequences. Some DUX4-activated MaLR and ERV elements create novel promoters for genes, long non-coding RNAs, and antisense transcripts. Many of these novel transcripts are expressed in FSHD muscle cells but not control cells, and thus might contribute to FSHD pathology. For example, HEY1, a repressor of myogenesis, is activated by DUX4 through a MaLR promoter. DUX4-bound motifs, including those in repetitive elements, show evolutionary conservation and some repeat-initiated transcripts are expressed in healthy testis, the normal expression site of DUX4, but more rarely in other somatic tissues. Testis expression patterns are known to have evolved rapidly in mammals, but the mechanisms behind this rapid change have not yet been identified: our results suggest that mobilization of MaLR and ERV elements during mammalian evolution altered germline gene expression patterns through transcriptional activation by DUX4. Our findings demonstrate a role for DUX4 and repetitive elements in mammalian germline evolution and in FSHD muscular dystrophy. RNA-seq of differentiated human primary myotube cell lines for FSHD patients and control samples Raw data not provided due to patient privacy concerns.

2014-03-19 | E-GEOD-51041 | biostudies-arrayexpress

Retroelements and DUX4 Create Primate-specific Promoters for Germline Genes

Project description:The human double-homeodomain retrogene DUX4 is normally expressed at high levels in germ cells of the testis. When aberrantly expressed in muscle its protein product causes facioscapulohumeral muscular dystrophy (FSHD), perhaps partly by inducing inappropriate expression of germline genes. DUX4 can bind >60,000 locations in the human genome that contain a strongly enriched sequence motif. Numerous long terminal repeat (LTR) class repetitive elements are enriched among DUX4 binding sites, including many from the mammalian apparent LTR-retrotransposon (MaLR) family as well as some ERVL and ERVK types, with MaLRs comprising ~1/3 of DUX4’s binding sites. We performed RNA-seq on myoblasts over-expressing DUX4 and find that DUX4 binding activates transcription of some but not all bound repeat types. Some of these activated repetitive elements comprise novel promoters for genes, long non-coding RNAs and antisense transcripts. We show that some of these chimeric repeat-initiated transcripts are expressed in testis and FSHD patient myotubes. The acquisition of MaLR-LTR elements during mammalian evolution may therefore have allowed rewiring of the transcriptional network. We also find that the pericentromeric satellite HSATII can be bound by DUX4 and that its transcription is massively induced by DUX4 over-expression. Our findings suggest a role for repetitive element transcripts in muscle disease and in the biology of normal testis.

2013-10-01 | GSE45883 | GEO

DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis.

2014-03-19 | GSE51041 | GEO

DUX4 activates germline genes, retroelements and immune-mediators: Implications for facioscapulohumeral dystrophy

Project description:Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression. [Overexpression experiment] Quadruplicate total RNA samples were collected from control human primary myoblasts transduced with lentivirus carrying DUX4-fl, DUX4-s or GFP (MOI = 15) for 24 h and from untransduced myoblasts. [Defensin experiment] Quadruplicate samples were also collected from myoblasts and myotubes grown in media containing human beta-defensin 3 peptide or in control media.

2012-01-03 | E-GEOD-33799 | biostudies-arrayexpress

DUX4 activates germline genes, retroelements and immune-mediators: Implications for facioscapulohumeral dystrophy

Project description:Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression. Examine Dux4 full isoform binding sites in human fibroblast.

2012-01-03 | E-GEOD-33838 | biostudies-arrayexpress

DUX4 activates germline genes, retroelements and immune-mediators: Implications for facioscapulohumeral dystrophy

2012-01-03 | GSE33838 | GEO

DUX4 activates germline genes, retroelements and immune-mediators: Implications for facioscapulohumeral dystrophy

2012-01-03 | GSE33799 | GEO

DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle

Project description:Facioscapulohumeral dystrophy (FSHD) is caused by decreased epigenetic repression of the D4Z4 macrosatellite array and recent studies have shown that this results in the expression of low levels of the DUX4 mRNA in skeletal muscle. Several other mechanisms have been suggested for FSHD pathophysiology and it remains unknown whether DUX4 expression can account for most of the molecular changes seen in FSHD. Since DUX4 is a transcription factor, we used RNA-seq to measure gene expression in muscle cells transduced with DUX4, and in muscle cells and biopsies from control and FSHD individuals. We show that DUX4 target gene expression is the major molecular signature in FSHD muscle together with a gene expression signature consistent with an immune cell infiltration. In addition, one unaffected individual without a known FSHD-causing mutation showed expression of DUX4 target genes. This individual has a sibling with FSHD and also without a known FSHD-causing mutation, suggesting the presence of yet unidentified modifier locus for DUX4 expression and FSHD. These findings demonstrate that expression of DUX4 accounts for the majority of the gene expression changes in FSHD skeletal muscle together with an immune cell infiltration. RNA-seq for muscle cells and biopsies from control and FSHD individuals.

2014-07-03 | E-GEOD-56787 | biostudies-arrayexpress

An allele-aware approach identifies altered nuclear associations of the contracted D4Z4 array at the FSHD locus

Project description:Facioscapulohumeral dystrophy (FSHD) is caused by a deletion in a D4Z4 macrosatellite repeat array in the 4q subtelomere that leads to somatic de-repression of the transcription factor DUX4. It is not fully understood how array contractions cause de-repression, but they alter the local chromatin structure of D4Z4, resulting in loss of heterochromatic markers. In order to determine whether pathogenic contractions also alter the nuclear organization of the FSHD locus, we designed an allele-aware, high-throughput circular chromosome conformation capture assay (4C-seq) that distinguishes the two 4q copies of the locus from each other and from a paralogous locus in the 10q subtelomere. Using a short sequence length polymorphism (SSLP) four kilobasepairs from the array as âharacterized the genomic contacts made by the four copies of the FSHD locus in muscle cell nuclei. The SSLP contacts predominate on the same chromosome arm as the bait, decaying rapidly beyond 30-40 Mb. Contacts on other chromosomes were enriched near centromeres and CTCF sites. We also found that the FSHD locus normally contacts regions adjacent to the nuclear lamina and with low overall gene expression. However, we found that the deleted locus in FSHD cells makes more contacts with regions with comparatively lower lamina adjacency and higher overall gene expression than in control cells. Furthermore, association of D4Z4 with components of the nuclear lamina was reduced in FSHD cells relative to control cells. Our results suggest that altered nuclear organization at 4q35 may be one factor in the de-repression of DUX4 in FSHD. 5 primary cells (2 control, 1 FSHD1, 1 FSHD2, and 1 FSHD3) were used to generate 4C libraries in biological duplicate, for a total of 10 4C libraries

2013-08-31 | E-GEOD-40673 | biostudies-arrayexpress

Conservation and innovation in the DUX4-family gene network [MMH6 RNA-Seq]

Project description:Facioscapulohumeral dystrophy (FSHD; OMIM #158900, #158901) is caused by mis-expression of the DUX4 transcription factor in skeletal muscle1. Animal models of FSHD are hampered by incomplete knowledge of the conservation of the DUX4 transcriptional program in other species. Despite divergence of their binding motifs, both mouse Dux and human DUX4 activate genes associated with cleavage-stage embryos, including MERV-L and ERVL-MaLR retrotransposons, in mouse and human muscle cells respectively. When expressed in mouse cells, human DUX4 maintained modest activation of cleavage-stage genes driven by conventional promoters, but did not activate MERV-L-promoted genes. These findings indicate that the ancestral DUX4-factor regulated genes characteristic of cleavage-stage embryos driven by conventional promoters, whereas divergence of the DUX4/Dux homeodomains correlates with retrotransposon specificity. These results provide insight into how species balance conservation of a core transcriptional program with innovation at retrotransposon promoters and provide a basis for animal models that recreate the FSHD transcriptome.

2017-02-01 | GSE93167 | GEO

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