Abstract
Knowledge of the diverse DNA binding specificities of transcription factors is important for understanding their specific regulatory functions in animal development and evolution. We have examined the genome-wide binding properties of the mouse HOXB1 protein in embryonic stem cells differentiated into neural fates. Unexpectedly, only a small number of HOXB1 bound regions (7%) correlate with binding of the known HOX cofactors PBX and MEIS. In contrast, 22% of the HOXB1 binding peaks display co-occupancy with the transcriptional repressor REST. Analyses revealed that co-binding of HOXB1 with PBX correlates with active histone marks and high levels of expression, while co-occupancy with REST correlates with repressive histone marks and repression of the target genes. Analysis of HOXB1 bound regions uncovered enrichment of a novel 15 base pair HOXB1 binding motif HB1RE (HOXB1 response element). In vitro template binding assays showed that HOXB1, PBX1, and MEIS can bind to this motif. In vivo, this motif is sufficient for direct expression of a reporter gene and over-expression of HOXB1 selectively represses this activity. Our analyses suggest that HOXB1 has evolved an association with REST in gene regulation and the novel HB1RE motif contributes to HOXB1 function in part through a repressive role in gene expression.
Highlights
Published: 3 February 2021The binding of transcription factors (TFs) at specific regulatory sequences in the genome underlies the control of gene expression and regulation of transcriptional networks essential for programming animal development and organogenesis and for modulating physiological and pathological processes [1,2]
How different HOX proteins, with similar in vitro DNA binding properties, regulate different developmental programs along the AP axis is poorly understood. We examined this question using ChIP-seq approaches to characterize the genome-wide binding properties of HOXA1 and HOXB1 proteins in mouse in embryonic stem (ES)
We focused on the characterization of one of the novel motifs enriched in the HOXB1 bound regions and named this 15-base pair motif HB1RE (HOXB1 response element)
Summary
The binding of transcription factors (TFs) at specific regulatory sequences in the genome underlies the control of gene expression and regulation of transcriptional networks essential for programming animal development and organogenesis and for modulating physiological and pathological processes [1,2]. Paralogous genes in highly conserved TF families may undergo changes resulting in altered functional activities and modified interactions between the TFs and their regulatory regions. This diversification of protein function and the adoption of novel roles have been implicated as a major driver in the evolution of phenotypic complexity, diversity and innovation [7,8,9,10,11]. Because DNA-binding motifs are in general relatively short sequence motifs (~8–15 bp), small changes in specific binding motifs can have a progressive and significant impact on the efficiency of binding by TFs, resulting in modifications of organismal phenotypes [12,13]
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