Deep molecular learning of transcriptional control of a synthetic CRE enhancer and its variants

Chan-Koo Kang; Ah-Ram Kim

doi:10.1016/j.isci.2023.108747

Deep molecular learning of transcriptional control of a synthetic CRE enhancer and its variants

iScience. 2023 Dec 15;27(1):108747. doi: 10.1016/j.isci.2023.108747. eCollection 2024 Jan 19.

Authors

Chan-Koo Kang^{1

2}, Ah-Ram Kim^{1

2

3

4}

Affiliations

¹ School of Life Science, Handong Global University, Pohang, Gyeong-Buk 37554, South Korea.
² Department of Advanced Convergence, Handong Global University, Pohang, Gyeong-Buk 37554, South Korea.
³ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ School of Applied Artificial Intelligence, Handong Global University, Pohang, Gyeong-Buk 37554, South Korea.

Abstract

Massively parallel reporter assay measures transcriptional activities of various cis-regulatory modules (CRMs) in a single experiment. We developed a thermodynamic computational model framework that calculates quantitative levels of gene expression directly from regulatory DNA sequences. Using the framework, we investigated the molecular mechanisms of cis-regulatory mutations of a synthetic enhancer that cause abnormal gene expression. We found that, in a human cell line, competitive binding between family transcription factors (TFs) with slightly different binding preferences significantly increases the accuracy of recapitulating the transcriptional effects of thousands of single- or multi-mutations. We also discovered that even if various harmful mutations occurred in an activator binding site, CRM could stably maintain or even increase gene expression through a certain form of competitive binding between family TFs. These findings enhance understanding the effect of SNPs and indels on CRMs and would help building robust custom-designed CRMs for biologics production and gene therapy.

Keywords: Artificial intelligence; Experimental models in systems biology; Molecular mechanism of gene regulation.