3D Chromatin Architecture, BRD4, and Mediator Have Distinct Roles in Regulating Genome-Wide Transcriptional Bursting and Gene Network

Authors

Pawel Trzaskoma
SeolKyoung Jung
Aleksandra Pękowska
Christopher H Bohrer
Xiang Wang
Faiza Naz
Stefania Dell'Orso
Wendy D Dubois
Ana Olivera
Supriya V Vartak
Yongbing Zhao
Subhashree Nayak
Andrew Overmiller
Maria I Morasso
Vittorio Sartorelli
Daniel R Larson
Carson C Chow
Rafael Casellas
John J O'Shea

Publication Date

8-9-2024

Journal

Science Advances

Abstract

Discontinuous transcription is evolutionarily conserved and a fundamental feature of gene regulation; yet, the exact mechanisms underlying transcriptional bursting are unresolved. Analyses of bursting transcriptome-wide have focused on the role of cis-regulatory elements, but other factors that regulate this process remain elusive. We applied mathematical modeling to single-cell RNA sequencing data to infer bursting dynamics transcriptome-wide under multiple conditions to identify possible molecular mechanisms. We found that Mediator complex subunit 26 (MED26) primarily regulates frequency, MYC regulates burst size, while cohesin and Bromodomain-containing protein 4 (BRD4) can modulate both. Despite comparable effects on RNA levels among these perturbations, acute depletion of MED26 had the most profound impact on the entire gene regulatory network, acting downstream of chromatin spatial architecture and without affecting TATA box-binding protein (TBP) recruitment. These results indicate that later steps in the initiation of transcriptional bursts are primary nodes for integrating gene networks in single cells.

Keywords

Chromatin, Transcription Factors, Gene Regulatory Networks, Cell Cycle Proteins, Humans, Transcription, Genetic, Gene Expression Regulation, Mediator Complex, Single-Cell Analysis, Transcriptome, Cohesins, Bromodomain Containing Proteins

Comments

Supplementary Materials

PMID: 39121214