
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.23.609430
preprint
1
Article
LDB1 establishes multi-enhancer networks to regulate gene expression
Aboreden Nicholas G. http://orcid.org/0000-0002-4154-048X

Lam Jessica C.
Goel Viraat Y.
Wang Siqing
Wang Xiaokang
Midla Susannah C.
Quijano Alma
Keller Cheryl A. http://orcid.org/0000-0001-6594-0245

Giardine Belinda M.
Hardison Ross C. http://orcid.org/0000-0003-4084-7516

Zhang Haoyue
Hansen Anders S. http://orcid.org/0000-0001-7540-7858

Blobel Gerd A.
24 8 2024
2024.08.23.609430https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.23.609430
nihpp-2024.08.23.609430.pdf
SUMMARY

How specific enhancer-promoter pairing is established is still mostly unclear. Besides the CTCF/cohesin machinery, only a few nuclear factors have been studied for a direct role in physically connecting regulatory elements. Here, we show via acute degradation experiments that LDB1 directly and broadly promotes enhancer-promoter loops. Most LDB1-mediated contacts, even those spanning hundreds of kb, can form in the absence of CTCF, cohesin, or YY1 as determined via the use of multiple degron systems. Moreover, an engineered LDB1-driven chromatin loop is cohesin independent. Cohesin-driven loop extrusion does not stall at LDB1 occupied sites but may aid the formation of a subset of LDB1 anchored loops. Leveraging the dynamic reorganization of nuclear architecture during the transition from mitosis to G1-phase, we establish a relationship between LDB1-dependent interactions in the context of TAD organization and gene activation. Lastly, Tri-C and Region Capture Micro-C reveal that LDB1 organizes multi-enhancer networks to activate transcription. This establishes LDB1 as a direct driver of regulatory network inter-connectivity.
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pmc
