Notch1 Phase Separation Coupled Percolation Facilitates Target Gene Expression and Enhancer Looping

Overview

Journal bioRxiv

Date 2024 Aug 12

PMID 39131356

Authors

Gregory Foran

Ryan Douglas Hallam

Marvel Megaly

Anel Turgambayeva

Daniel Antfolk

Yifeng Li

Vincent C Luca

Aleksandar Necakov

Affiliations

Soon will be listed here.

Abstract

The Notch receptor is a pleiotropic signaling protein that translates intercellular ligand interactions into changes in gene expression the nuclear localization of the Notch intracellular Domain (NICD). Using a combination of immunohistochemistry, RNA , Optogenetics and super-resolution live imaging of transcription in human cells, we show that the N1ICD can form condensates that positively facilitate Notch target gene expression. We determined that N1ICD undergoes Phase Separation Coupled Percolation (PSCP) into transcriptional condensates, which recruit, enrich, and encapsulate a broad set of core transcriptional proteins. We show that the capacity for condensation is due to the intrinsically disordered transcriptional activation domain of the N1ICD. In addition, the formation of such transcriptional condensates acts to promote Notch-mediated super enhancer-looping and concomitant activation of the MYC protooncogene expression. Overall, we introduce a novel mechanism of Notch1 activity in which discrete changes in nuclear N1ICD abundance are translated into the assembly of transcriptional condensates that facilitate gene expression by enriching essential transcriptional machineries at target genomic loci.

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