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Wide-ranging fucntions of E2F4 in transcriptional activation and repression revealed by genome-wide analysis

ABSTRACT: The transcription factor E2F4 is a member of the E2F family of regulators which has critical roles in cell cycle control and differentiation. We investigated the genome-wide binding profile of E2F4 using a newly developed peak calling program based on a kernel density estimation and identified approximately 16 thousands E2F4 binding sites at a 1% FDR threshold, which potentially modulate 7,346 downstream target genes. Gene Ontology (GO) functional analysis of E2F4 target genes revealed several novel functions of E2F4 including I-kappaB kinase/NF-kappaB cascade, protein transport and targeting, protein folding, and sterol biosynthetic process. In addition to mRNA target genes, E2F4 also binds and regulates some miRNA targets such as let-7a, mir-17 and mir-22. Interestingly, we found that about 20% of E2F4 sites are in intergenic regions, which suggests that E2F4 may function at enhancer sites. De novo motif discovery revealed 5 novel, significantly enriched motifs within E2F4 sites. Only 5% of binding sites contain a canonical motif, indicating that E2F4 can use diverse motifs to bind DNA and regulate transcription. Overexpression of E2F4 and its cofactors such as RBL2 and DP-1, followed by microarray analysis, revealed that E2F4 functions as an activator and a repressor. Taken together, our genome-wide E2F4 ChIP sequencing data provided evidences of versatile physiological roles of E2F4 and insights into its functions. This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE21489 | GEO | 2010/11/01

SECONDARY ACCESSION(S): PRJNA126027

REPOSITORIES: GEO

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Project description:CTCF (CCCTC-binding factor) is a highly conserved 11-zinc finger DNA binding protein with tens of thousands of binding sites genome-wide. CTCF acts as a multifunctional regulator of transcription, having been previously associated with activator, repressor, and insulator activity. These diverse regulatory functions are crucial for preimplantation development and are implicated in the regulation of numerous lineage-specific genes. Despite playing a critical role in developmental gene regulation, the mechanisms that underlie developmental changes in CTCF recruitment and function are poorly understood. Our previous work suggested that differences in CTCFM-bM-^@M-^Ys binding site sequence may affect the regulation of CTCF recruitment, as well as CTCFM-bM-^@M-^Ys regulatory function. To investigate these two possibilities directly during a developmental process, changes in genome-wide CTCF binding and gene expression were characterized during in vitro differentiation of mouse embryonic stem cells. CTCF binding sites were initially separated into three classes (named LowOc, MedOc, and HighOc) based on similarity to the consensus motif. The LowOc class, with lower-similarity to the consensus motif, is more likely to show changes in binding during differentiation. These more dynamically bound sites are enriched for motifs that confer a lower in vitro affinity for CTCF, suggesting a mechanism where sites with low-binding affinity are more amenable to developmental control. Additionally, by comparing changes in CTCF binding with changes in gene expression during differentiation, we show that LowOc and HighOc sites are associated with distinct regulatory functions. In sum, these results suggest that the regulatory control of CTCFM-bM-^@M-^Ys binding and function is dependent in part upon specific motifs within its DNA binding site. Mouse E14 ES cells were differentiated in vitro for 4.5 days using retinoic acid. RNA-Seq was performed from cells collected before and after differentiation.

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Wide-ranging fucntions of E2F4 in transcriptional activation and repression revealed by genome-wide analysis

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