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Vertebrate GAGA factor associated insulator elements demarcate homeotic genes in the HOX clusters

ABSTRACT: Hox genes impart segment identity to body structures along the anterior-posterior axis and are crucial for the proper development of all organisms. Multiple regulatory elements, best defined in Drosophila melanogaster, ensure that Hox expression patterns follow the spatial and temporal colinearity reflected in their tight genomic organization. However, the precise mechanisms that regulate colinear patterns of Hox gene expression remain unclear, especially in higher vertebrates where it is not fully determined how the distinct activation domains of the tightly clustered Hox genes are defined independent of each other. Here, we report the identification of a large number of novel cis-elements at mammalian Hox clusters that can help in regulating their precise expression pattern.

ORGANISM(S): Mus musculus

PROVIDER: GSE42941 | GEO | 2013/05/01

SECONDARY ACCESSION(S): PRJNA183900

REPOSITORIES: GEO

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Vertebrate GAGA factor associated insulator elements demarcate homeotic genes in the HOX clusters

Project description:Hox genes impart segment identity to body structures along the anterior-posterior axis and are crucial for the proper development of all organisms. Multiple regulatory elements, best defined in Drosophila melanogaster, ensure that Hox expression patterns follow the spatial and temporal colinearity reflected in their tight genomic organization. However, the precise mechanisms that regulate colinear patterns of Hox gene expression remain unclear, especially in higher vertebrates where it is not fully determined how the distinct activation domains of the tightly clustered Hox genes are defined independent of each other. Here, we report the identification of a large number of novel cis-elements at mammalian Hox clusters that can help in regulating their precise expression pattern. Agilent two-color ChIP-on-Chip experiment, Organism: Mus musculus ,Genotypic Technology designed Custom Mouse 1 million ChIP-on-chip Array (AMADID-0245671)

2013-05-01 | E-GEOD-42941 | biostudies-arrayexpress

Vertebrate GAGA factor associated insulator elements demarcate homeotic genes in the HOX clusters.

Project description: Not available

| S-EPMC3639804 | biostudies-other

SET1A/COMPASS and shadow enhancers in the regulation of homeotic gene expression

Project description:The homeotic (Hox) genes are highly conserved in metazoans, where they are required for various processes in development and misregulation of their expression is associated with human cancer. In the developing embryo, Hox genes are sequentially activated in time and space according to their genomic position within Hox gene clusters. Accumulating evidence implicates both enhancer elements and non-coding RNAs in controlling this spatiotemporal expression of Hox genes, but disentangling their relative contributions is challenging. Here, we identify two cis-regulatory elements (E1 and E2) functioning as shadow enhancers to regulate the early expression of the HoxA genes. Simultaneous deletion of these shadow enhancers in embryonic stem cells leads to impaired activation of HoxA genes upon differentiation, while knockdown of a long non-coding RNA overlapping E1 has no detectable effect on their expression. Although MLL/COMPASS family of histone methyltransferases are known to activate transcription of Hox genes in other contexts, we find that individual inactivation of the MLL1-4/COMPASS family members has little effect on early Hox gene activation. Instead, we demonstrate that SET1A/COMPASS is required for full transcriptional activation of multiple Hox genes, but functions independently of the E1 and E2 cis-regulatory elements. Our results reveal multiple regulatory layers for Hox genes to fine-tune transcriptional programs essential for development.

2017-05-09 | GSE98140 | GEO

Comparison of genome-wide distribution of histone modifications (H3K4me3, H3K9me2, H3K27me2, and H3K27me3) between wild-type and Kdm7a mutant embryos

Project description:Temporal and spatial colinear expression of Hox genes determines the specification of positional identities of the embryo. Post-translational modifications of histones contribute to transcriptional regulation, and are required for proper control of biological processes, including differentiation and development. Lysine demethylase 7A (Kdm7a) demethylates lysine 9 di-methylation of histone H3 (H3K9me2) and participates in transcriptional activation of developmental genes. However, the role of Kdm7a during mouse embryonic development remains to be elucidated. Here, we show that Kdm7a-/- mice exhibit anterior homeotic transformation of the axial skeleton (i.e. an increase in the number of presacral elements). Importantly, posterior Hox genes (caudally from Hox9) are specifically down-regulated in Kdm7a-/- embryos, which correlate with increased levels of H3K9me2. Taken together, these data suggest that Kdm7a is able to control transcription of posterior Hox genes, likely through its demethylating activity, and thereby regulating anterior-posterior development in mice.

2019-12-23 | GSE133188 | GEO

Comparison of gene expression profiles between wild-type and Kdm7a mutan embryos

2019-12-23 | GSE133187 | GEO

Interaction between the GAGA factor and Mod(mdg4) proteins promotes insulator bypass in Drosophila.

Project description: Not available

| S-EPMC522021 | biostudies-literature

HOX epi-mutations, driven by maternal SMCHD1 or LRIF1 haploinsufficiency, trigger homeotic transformations in genetically wildtype offspring

Project description:The body plan of animals is laid out by an evolutionary-conserved HOX code which is colinearly transcribed after zygotic genome activation (ZGA). Here we report that SMCHD1, a chromatin-modifying enzyme needed for X-inactivation in mammals, is maternally required for timely HOX expression. Using zebrafish and mouse Smchd1 knockout animals, we demonstrate that Smchd1 haplo-insufficiency brings about precocious and ectopic HOX transcription during oogenesis and embryogenesis. Unexpectedly, wild-type offspring born to heterozygous knockout zebrafish smchd1 mothers exhibited patent vertebrate patterning defects. The loss of maternal Smchd1 was accompanied by HOX epi-mutations driven by aberrant DNA methylation. We further show that this regulation is mediated by Lrif1, a direct interacting partner of Smchd1, whose knockout in zebrafish phenocopies that of Smchd1. Rather than being a short-lived maternal effect, HOX mis-regulation is stably inherited through cell divisions and persists in cultured fibroblasts derived from patients haploinsufficient for SMCHD1. We conclude that maternal Smchd1/Lrif1 sets up an epigenetic state in the HOX loci that can only be reset in the germline. Such an unusual inter-generational inheritance, whereby a phenotype can be one generation removed from its genotype, casts a new light on how unresolved Mendelian diseases may be interpreted.

2022-05-25 | GSE173462 | GEO

The cis-regulatory code of Hox function in Drosophila

Project description:Precise gene expression is a fundamental aspect of organismal function and depends on the combinatorial interplay of transcription factors (TFs) with cis‐regulatory DNA elements. While much is known about TF function in general, our understanding of their cell type‐specific activities is still poor. To address how widely expressed transcriptional regulators modulate downstream gene activity with high cellular specificity, we have identified binding regions for the Hox TF Deformed (Dfd) in the Drosophila genome. Our analysis of architectural features within Hox cis‐regulatory response elements (HREs) shows that HRE structure is essential for cell type‐specific gene expression. We also find that Dfd and Ultrabithorax (Ubx), another Hox TF specifying different morphological traits, interact with non‐overlapping regions in vivo, despite their similar DNA binding preferences. While Dfd and Ubx HREs exhibit comparable design principles, their motif compositions and motif‐pair associations are distinct, explaining the highly selective interaction of these Hox proteins with the regulatory environment. Thus, our results uncover the regulatory code imprinted in Hox enhancers and elucidate the mechanisms underlying functional specificity of TFs in vivo.

2015-09-29 | GSE73493 | GEO

GAGA-Associated Factor Fosters Loop Formation in the Drosophila Genome

Project description:The role of genome organization in the control of gene expression persists as a central mystery of modern biology. Most efforts have focused on the role of boundary elements and CTCF in the compartmentalization of the genome into a series of topological associating domains (TADs). These compartments have been suggested to enable long-range DNA-DNA associations via loop extrusion processes. However, there is emerging evidence for long-range focal contacts, whereby specific DNA sequences associated with promoters and distal enhancers interact to form chromatin loops. One such class of DNAs, tethering elements, binds GAGA-associated factor (GAF). Previous studies provided evidence that GAF possesses amyloid properties in vitro, enabling the formation of loops bridging separate DNA molecules. In this study we investigated the possibility that GAF also functions as a looping factor in Drosophila development. We employed a combination of Micro-C assays, proteasomal degradation, and genome editing to examine the impact of defined GAF mutants on genome topology. These studies suggest that the N-terminal POZ/BTB oligomerization domain is particularly important for long-range interactions of GAF bound to distant GAGA-rich tethering elements. By contrast, the C-terminal low complexity domain (poly Q) plays only a minor role in loop formation. The most striking effects of GAF mutants are observed for long-range promoter-promoter interactions that coordinate the activities of distant paralogous genes.

2023-02-14 | GSE218168 | GEO

Co-localization of Polycomb protein and GAGA factor on regulatory elements responsible for the maintenance of homeotic gene expression.

Project description: Not available

| S-EPMC1169986 | biostudies-other