A -regulatory Lexicon of DNA Motif Combinations Mediating Cell-type-specific Gene Regulation

Overview

Journal Cell Genom

Date 2023 Feb 6

PMID 36742369

Authors

Laura K H Donohue

Margaret G Guo

Yang Zhao

Namyoung Jung

Rose T Bussat

Daniel S Kim

Poornima H Neela

Laura N Kellman

Omar S Garcia

Robin M Meyers

Russ B Altman

Paul A Khavari

Affiliations

Soon will be listed here.

Abstract

Gene expression is controlled by transcription factors (TFs) that bind cognate DNA motif sequences in -regulatory elements (CREs). The combinations of DNA motifs acting within homeostasis and disease, however, are unclear. Gene expression, chromatin accessibility, TF footprinting, and H3K27ac-dependent DNA looping data were generated and a random-forest-based model was applied to identify 7,531 cell-type-specific -regulatory modules (CRMs) across 15 diploid human cell types. A co-enrichment framework within CRMs nominated 838 cell-type-specific, recurrent heterotypic DNA motif combinations (DMCs), which were functionally validated using massively parallel reporter assays. Cancer cells engaged DMCs linked to neoplasia-enabling processes operative in normal cells while also activating new DMCs only seen in the neoplastic state. This integrative approach identifies cell-type-specific -regulatory combinatorial DNA motifs in diverse normal and diseased human cells and represents a general framework for deciphering -regulatory sequence logic in gene regulation.

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