Combinatorial Action of Temporally Segregated Transcription Factors

Julien Charest,Luisa Cochella,Thomas Daniele,Mila Asparuhova,Paula Gutiérrez-Pérez,Ariane Mandlbauer,Josef Röhsner,Jingkui Wang,Aleksandr Bykov

doi:10.1016/j.devcel.2020.09.002

Abstract

SummaryCombinatorial action of transcription factors (TFs) with partially overlapping expression is a widespread strategy to generate novel gene-expression patterns and, thus, cellular diversity. Known mechanisms underlying combinatorial activity require co-expression of TFs within the same cell. Here, we describe the mechanism by which two TFs that are never co-expressed generate a new, intersectional expression pattern in C. elegans embryos: lineage-specific priming of a gene by a transiently expressed TF generates a unique intersection with a second TF acting on the same gene four cell divisions later; the second TF is expressed in multiple cells but only activates transcription in those where priming occurred. Early induction of active transcription is necessary and sufficient to establish a competent state, maintained by broadly expressed regulators in the absence of the initial trigger. We uncover additional cells diversified through this mechanism. Our findings define a mechanism for combinatorial TF activity with important implications for generation of cell-type diversity.

Highlights

Transcription of developmentally regulated genes typically requires combinatorial activity of multiple transcription factors (TFs)
Binding of TBX-37/38 Is Necessary and Sufficient to Prime lsy-6 To begin to dissect the mechanism by which TBX-37/38 contribute to the specific expression of lsy-6 in the post-mitotic ASEL, we explored the possibility that these TFs bind directly to the lsy-6 locus already at the 28-cell stage, when they are first detected
We generated gfp-tagged alleles of endogenous tbx37 or -38 using CRISPR-Cas9 (Figure S1A). Because these TFs are almost identical in sequence and fully redundant (Good et al, 2004), we tagged each TF in the background of a deletion of its paralog, such that the only source of TBX factor is tagged with GFP

Summary

Introduction

Transcription of developmentally regulated genes typically requires combinatorial activity of multiple transcription factors (TFs). Combinatorial use of TFs enables the generation of novel, specific gene-expression patterns that exceed the number of available TFs, through creation of intersectional gene-expression domains (Figure 1A, left) (Allan and Thor, 2015; Reiter et al, 2017; Spitz and Furlong, 2012). Known cases of combinations of TFs to generate cell-type diversity during development rely on spatial intersection of TFs with partially overlapping expression patterns (Figure 1A, left) (Alaynick et al, 2011; Wenick and Hobert, 2004; Xue et al, 1993; Zhang et al, 2014)

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Discussion

Conclusion