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Related Concept Videos

Cis-regulatory Sequences02:02

Cis-regulatory Sequences

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Cis-regulatory sequences are short fragments of non-coding DNA that are present on the same chromosomes as the genes that they regulate. These fragments serve as binding sites for transcriptional regulators, proteins that are responsible for controlling gene transcription and differential gene expression across cell types in eukaryotes. Cis-regulatory sequences can be close to the gene of interest or thousands of bases away in the DNA sequence; however, those sequences that are further away are...
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Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome.  Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form...
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Next-generation sequencing technologies have created large genomic databases of a variety of animals and plants. Ever since the human genome project was completed, scientists studied the genome of primates, mammals, and other phylogenetically distant living beings. Such large-scale  studies have provided new insights into the evolutionary relationship between organisms.
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The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
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High-throughput Identification of Gene Regulatory Sequences Using Next-generation Sequencing of Circular Chromosome Conformation Capture 4C-seq
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Deconvolving sequence features that discriminate between overlapping regulatory annotations.

Akshay Kakumanu1, Silvia Velasco2, Esteban Mazzoni2

  • 1Center for Eukaryotic Gene Regulation, Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, PA, United States of America.

Plos Computational Biology
|October 20, 2017
PubMed
Summary
This summary is machine-generated.

SeqUnwinder deconvolves sequence features from overlapping regulatory DNA labels. This method distinguishes cell-type specific transcription factor binding from promoter proximity effects, enabling nuanced genomic analysis.

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Area of Science:

  • Genomics
  • Computational Biology
  • Bioinformatics

Background:

  • Genomic loci possess regulatory potential, annotated by properties like proximity to promoters and cell-type specific activity.
  • Overlapping annotations between genomic sites (e.g., cell-type specific activity and promoter proximity) confound the discovery of label-specific sequence features.
  • Distinguishing sequence features associated with distinct biological labels is crucial for understanding gene regulation.

Purpose of the Study:

  • To develop a principled computational approach, SeqUnwinder, for deconvoluting interpretable sequence features from overlapping genomic annotation labels.
  • To address the challenge of confounding factors in identifying sequence motifs associated with specific biological conditions or cell types.
  • To enable accurate characterization of sequence properties linked to distinct regulatory elements.

Main Methods:

  • Developed SeqUnwinder, a novel computational method designed to disentangle sequence features associated with overlapping annotation labels.
  • Applied SeqUnwinder to analyze transcription factor (TF) binding dynamics during motor neuron programming.
  • Utilized SeqUnwinder to characterize sequence properties of cell-specific and multi-condition TF binding sites, controlling for promoter proximity.

Main Results:

  • SeqUnwinder successfully unraveled sequence features related to dynamic TF binding during motor neuron programming, separating them from embryonic stem cell chromatin states.
  • The method identified distinct sequence properties of cell-specific and multi-condition TF binding sites, accounting for promoter proximity biases.
  • Demonstrated the scalability of SeqUnwinder by discovering cell-specific sequence features from over 100,000 genomic loci identified through DNase I hypersensitivity in ENCODE cell lines.

Conclusions:

  • SeqUnwinder provides a robust framework for deconvoluting sequence features from complex, overlapping genomic annotations.
  • The approach enhances the ability to identify true sequence determinants of cell-type specific and condition-specific gene regulation.
  • SeqUnwinder is a scalable and powerful tool for large-scale genomic data analysis, facilitating discoveries in regulatory genomics.