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Eukaryotic transcription factors (TFs) form complexes with various partner proteins to recognize their genomic target sites. Yet, how the DNA sequence determines which TF complex forms at any given site is poorly understood. Here, we demonstrate that high-throughput in vitro DNA binding assays coupled with unbiased computational analysis provide unprecedented insight into how different DNA sequences select distinct compositions and configurations of homeodomain TF complexes. Using inferred knowledge about minor groove width readout, we design targeted protein mutations that destabilize homeodomain binding both in vitro and in vivo in a complex-specific manner. By performing parallel systematic evolution of ligands by exponential enrichment sequencing (SELEX-seq), chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing (RNA-seq), and Hi-C assays, we not only classify the majority of in vivo binding events in terms of complex composition but also infer complex-specific functions by perturbing the gene regulatory network controlled by a single complex.
This article was published in the following journal.
Name: Molecular cell
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A TALE-type homeodomain protein and transcription factor that binds the DNA sequence 5'-ATCAATCAA-3'. It forms a heterodimer with MEIS1 TRANSCRIPTION FACTOR and functions as a transcriptional activator of HOMEOBOX PROTEIN NKX-2.5 and ELONGIN A, and as a transcriptional repressor of CDKN2B PROTEIN, in the regulation of developmental and morphogenetic processes such as spleen and limb development. Chromosome translocations involving the PBX1 and TCF3 genes occur in cases of pre-B-cell ACUTE LYMPHOID LEUKEMIA.
ATP-dependent DNA helicase that contains two N-terminal ZINC FINGERS and C-terminal ATP-binding and helicase domains. It functions in the regulation of gene transcription and CHROMATIN REMODELING. ATRX undergoes cell-cycle dependent phosphorylation, which causes it to translocate from the NUCLEAR MATRIX to CHROMATIN; thus, it may change its role from gene regulation during INTERPHASE to ensuring proper chromosome segregation at MITOSIS. Mutations in the ATRX gene are associated with cases of X-LINKED MENTAL RETARDATION co-morbid with ALPHA-THALASSEMIA (ATRX syndrome).
Proteins encoded by homeobox genes (GENES, HOMEOBOX) that exhibit structural similarity to certain prokaryotic and eukaryotic DNA-binding proteins. Homeodomain proteins are involved in the control of gene expression during morphogenesis and development (GENE EXPRESSION REGULATION, DEVELOPMENTAL).
A basic helix-loop-helix transcription factor that plays a role in determining cell fate during embryogenesis. It forms a heterodimer with TWIST TRANSCRIPTION FACTOR and ACHAETE-SCUTE GENE COMPLEX-related TRANSCRIPTION FACTORS.
An antennapedia-like homeodomain transcription factor that regulates the expression of multiple genes in the INTESTINAL MUCOSA. It plays a critical role in many processes from early differentiation to maintenance of the intestinal epithelial lining of both the small and large intestine.
Bioinformatics is the application of computer software and hardware to the management of biological data to create useful information. Computers are used to gather, store, analyze and integrate biological and genetic information which can then be applied...
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Commercial and academic collaborations are used throughout the biotechnology and pharmaceutical sector to enhance research and product development. Collaborations can take the form of research and evaluation agreements, licensing, partnerships etc. ...