Biochemical controls: controlling DNA transcriptions (Introduction)

by David Turell , Friday, April 26, 2024, 15:56 (209 days ago) @ David Turell

New work to uncover all the various steps and controls:

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/26_april_2024/41907...

"The central dogma of molecular biology outlines the flow of genetic information from DNA to RNA to proteins. With a limited vocabulary of four nucleotides (A, C, G, and T), DNA encodes an extensive instruction set, including the chromosomal positions where RNAs begin to be transcribed and the magnitudes of their expression. This process, known as transcription initiation, begins at transcription start sites (TSSs) and depends on RNA polymerase II recruitment to promoter sequences. However, the sequences and rules that govern transcription initiation remain elusive. On page 405 of this issue, Dudnyk et al. use an explainable deep-learning model to find a small set of DNA sequence motifs that predict the position and activity of most TSSs in the human genome. The findings define a set of rules that govern transcription initiation and highlight the potential of using deep-learning approaches to understand how information is genetically encoded.

"The advancement of DNA sequencing technologies has enabled the high-quality, genome-wide identification of TSSs, which has helped to elucidate transcription in mammalian genomes. Cap analysis of gene expression (CAGE) is one such technology that measures both the location and strength of TSSs. About two decades ago, the first large-scale CAGE analysis comprehensively defined TSSs in both mouse and human genomes, unveiling previously unknown features of promoter architecture and the complexity of transcriptional regulation. Complementing CAGE, global run-on sequencing (GRO-seq) technology was developed to track RNA polymerase activity throughout the entire transcription process, including initiation, elongation, and termination. GRO-seq revealed widespread occurrences of polymerase pausing and bidirectional transcription initiation events at promoters. Building on GRO-seq, precision nuclear run-on and sequencing (PRO-seq) enhanced the mapping of actively transcribing polymerase to single-nucleotide resolution, providing an in-depth comprehension of the interplay between RNA polymerase pausing and promoter structure.

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"The rules rely on three types of sequence patterns: motifs, initiators, and trinucleotides. The nine motifs are the main drivers of transcription initiation signals and can have short- or long-distance effects. The 11 initiators fine-tune transcription initiation signals but only have local effects. The 32 trinucleotides (representing all three-nucleotide combinations of A, C, G, and T) account for the remaining sequence dependencies not captured by motifs and initiators and have mostly local effects.

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"Understanding the regulatory grammar encoded within DNA sequences and deciphering the combinatorial interactions among motifs are fundamental challenges in unraveling genomic function. The study of Dudnyk et al. illustrates how targeted efforts to build high-resolution, genome-wide datasets can empower deep-learning approaches to address these challenges. This general strategy serves as a paradigm that is poised to unravel the mysteries of other fundamental gene regulatory functions encoded in nucleic acid sequences."

Comment: note the final paragraph. DNA translations are a tightly controlled process. Note this from the paper: " Deciphering these rules enabled the model to make specific inferences about various scenarios, such as the transcriptional outcome if a specific protein that binds the sequence pattern is lost. These computational predictions were supported by experimental data. Moreover, many of the rules appeared to be widely conserved across 241 mammalian species, with independent models trained on either human or mouse data and generalizing well in their predictions on data from other species." (my bold) The findings support what one might suspect. DNA transcription controls are precise and tight.