Analysis of the Drosophila and Human DPR Elements Reveals a Distinct Human Variant Whose Specificity Can Be Enhanced by Machine Learning

Aug 3, 2026

RNA polymerase II core promoter sequences integrate regulatory cues that initiate transcription. This research performs a comparative, machine-learning-based analysis of downstream core promoter region (DPR) elements in Drosophila and humans. The work identifies a distinct human-specific DPR variant and leverages machine learning to discover synthetic extreme DPR motifs with factor-specific specificity between human and Drosophila transcription factors. More broadly, the models support designing synthetic DNA elements with customized functional properties.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages43

Reading Time1 h 48 min

AccessFree to download

Abstract

Transcription initiation and core promoter elements

RNA polymerase II core promoter

Sequence motifs and prediction challenges

Two-step SVR and HARPE strategy

HARPE high-throughput analysis

Support vector regression models

Comparative analysis of DPR in humans and Drosophila

Generating DPR models and insights

Results & Discussion

SVR model predicts DPR activity in Drosophila

UC San Diego UC San Diego Previously Published Works Title Analysis of the Drosophila and human DPR elements reveals a distinct human variant whose specificity can be enhanced by machine learning Permalink [https://escholarship.org/uc/item/1rt3r053](https://escholarship.org/uc/item/1rt3r053) Journal Genes & Development, 37(9-10) ISSN 0890-9369 Authors Vo Ngoc, Long Rhyne, Torrey EKadonaga, James T Publication Date 2023-05-01 DOI 10.1101/gad.350572.123 Copyright Information This work is made available under the terms of a Creative Commons AttributionNonCommercial-NoDerivatives License, available at [https://creativecommons.org/licenses/by-nc-nd/4.0/](https://creativecommons.org/licenses/by-nc-nd/4.0/) Peer reviewed [eScholarship.org](eScholarship.org) Powered by the California Digital Library University of California Vo ngoc et al. (Kadonaga) 1 RESEARCH COMMUNICATION Analysis of the Drosophila and Human DPR Elements Reveals a Distinct Human Variant Whose Specificity Can Be Enhanced by Machine Learning Long Vo ngoc , 1,2,3 Torrey E. Rhyne , 1,3 and James T. Kadonaga 1,4 [Key words: Transcription, RNA Polymerase II, Core Promoter, Gene Expression , Drosophila] Running Head: Enhancing DNA element specificity by using AI 1 Department of Molecular Biology, University of California, San Diego, La Jolla, California 92093 , USA; 2Current address: Velia Therapeutics, San Diego, California 92130. 3These authors contributed equally to this work 4Corresponding author: [jkadonaga@ucsd.edu](jkadonaga@ucsd.edu) Vo ngoc et al. (Kadonaga) 2 Abstract The RNA polymerase II core promoter is the site of convergence of the signals that lead to the initiation of transcription. Here, we perform a comparative analysis of the downstream core promoter region (DPR) in Drosophila and humans by using machine learning. These studies revealed a distinct human-specific version of the DPR and led to the use of machine learning models for the identification of synthetic extreme DPR motifs with specificity for human transcription factors relative to Drosophila factors, and vice versa. More generally, machine learning models could similarly be used to design synthetic DNA elements with customized functional properties. Vo ngoc et al. (Kadonaga) 3 The initiation of transcription by RNA polymerase II is an important step in the expression of genes (see, for example: Cramer 2019, Galouzis and Furlong 2022, Haberle et al. 2018, Roeder 2019, Schier and Taatjes 2020, Sloutskin et al. 2021, Vo ngoc et al. 2019 , Zeitlinger 2020) . Transcription initiates at the core promoter, which comprises the stretch of DNA from about −40 to +40 relative to the +1 transcription start site (TSS) . The core promoter is often referred to asthe "gateway to transcription", as it is the site of convergence of the signals that direct the initiation of transcription. Core promoter activity is driven by DNA sequence elements such asthe TATA box, initiator (Inr) , and downstream promoter region (DPR) , which is the revised name for the combined motif ten element (MTE; Lim et al. 2004) and downstream core promoter element (DPE; Burke and Kadonaga 1996) from +17 to +35 relative to the +1 TSS (Vo ngoc et al. 2020) . There are no universal core promoter elements. Moreover, individual core promoter motifs are involved in transcriptional regulatory functions such as enhancer-core promoter specificity (see, for example, Ohtsuki et al. 1998, Butler and Kadonaga 2001 , Zabidi et al. 2015 , Galouzis and Furlong 2022) . A key challenge in the study of the core promoter has been the ability to predict the existence and activity of particular core promoter elements. In the past , the presence of core promoter motifs has been generally assessed by the similarity of the DNA sequences to consensus sequences, such as TATAAA for the TATA box. This method can lead to the incorrect assignments of motifs and also does not provide a quantitative p

FAQs

What is the core promoter and why is it important for transcription initiation?

The RNA polymerase II core promoter is the convergence point for signals that drive transcription initiation. It includes DNA sequence elements such as TATA box, Inr, and DPR, which shape transcriptional regulation.

How does the study use machine learning to analyze DPR elements?

The authors generate high-throughput HARPE data for randomized promoter variants and use the resulting measurements to train support vector regression (SVR) models. These models provide quantitative predictions of transcription strength for test DNA sequences.

What key finding emerges from the comparative DPR analysis between humans and Drosophila?

The analysis reveals a distinct human-specific DPR variant. This discovery enables the use of SVR models to design synthetic DPR motifs with customized specificity for human versus Drosophila transcription factors.

Aug 3, 2026

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