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Genome-wide binding of posterior HOXA/D transcription factors reveals subgrouping and association with CTCF [RNA-Seq]

ABSTRACT: The homeotic genes (Hox genes) encode transcription factors (HOX-TFs) that are key regulators of animal development. Single and compound deletion of Hox genes in mice revealed that they act in a partially redundant manner to pattern the vertebrate limb. Biochemical screens probing the sequence specificity of the DNA-binding domains showed that HOX-TFs recognize largely similar DNA sequences, but also emphasized the important role of co-factors in HOX DNA-binding. However, due to their high sequence homology and overlapping expression patterns, little is known about the genome-wide binding of these transcription factors Here, we set out to systematically compare the effects of the nine limb-bud expressed HOX-TFs on cell differentiation and gene regulation, and compare their genome-wide binding characteristics. We find that HOX-TFs induce distinct regulatory programs in transduced cells. Through genome-wide DNA binding profiling we find that the posterior HOX-TFs can be separated into two groups with distinct binding motifs and association with co-factors. Through this unexpected grouping, we characterize the CCCTC-binding factor (CTCF) as a novel co-factor of HOX-TFs and show that one, but not the other group of HOX-TFs binds to thousands of CTCF-occupied sites in the chicken genome.

ORGANISM(S): Gallus gallus

PROVIDER: GSE85757 | GEO | 2016/12/31

SECONDARY ACCESSION(S): PRJNA339275

REPOSITORIES: GEO

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Project description:ChIP-Sequencing on Shox2-HA E12.5 and E13.5 Limb and Palate, as well as Pbx on E12.5 limb . Abstract: Vertebrate appendage patterning is programmed by Hox-TALE factors-bound regulatory elements. However, it remains enigmatic which cell lineages are commissioned by Hox-TALE factors to generate regional specific pattern and whether other Hox-TALE co-factors exist. In this study, we investigated the transcriptional mechanisms controlled by the Shox2 transcriptional regulator in limb patterning. Harnessing an osteogenic lineage-specific Shox2 inactivation approach we show that despite widespread Shox2 expression in multiple cell lineages, lack of the stylopod observed upon Shox2 deficiency is a specific result of Shox2 loss of function in the osteogenic lineage. ChIP-Seq revealed robust interaction of Shox2 with cis-regulatory enhancers clustering around skeletogenic genes that are also bound by Hox-TALE factors, supporting a lineage autonomous function of Shox2 in osteogenic lineage fate determination and skeleton patterning. Pbx ChIP-Seq further allowed the genome-wide identification of cis-regulatory modules exhibiting co-occupancy of Pbx, Meis, and Shox2 transcriptional regulators. Integrative analysis of ChIP-Seq and RNA-Seq data and transgenic enhancer assays indicate that Shox2 patterns the stylopod as a repressor via interaction with enhancers active in the proximal limb mesenchyme and antagonizes the repressive function of TALE factors in osteogenesis. Shox2/TALE For ChIP-Seq, the list of libraries below, including controls, were generated [listed in the format of (antibody)-target-tissue-stage]: (Î±-HA)-Shox2-Limb-E12.5, (Î±-HA)-Shox2-Limb-E13.5, (Î±-HA)-Shox2-Palate-E12.5, (Î±-HA)-Shox2-Limb/Palate-E12.5, (Î±-Pbx)-Pbx-Limb-E12.5, Input (control), (Î±-HA)-Mixed Limb/Palate from Shox2+/+ mice-E12.5 (control). *The attached signal tracks(*.bigwig) were generated by âbdgcmp (MACS2) to filter out background signal(by filtering against the signal track obtained from (Î±-HA)-Mixed Limb/Palate from Shox2+/+ mice-E12.5 (control)) and subsequently convert to bigwig for analysis and visualization.

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Genome-wide binding of posterior HOXA/D transcription factors reveals subgrouping and association with CTCF [RNA-Seq]

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