2. Academic Validation
  3. LDB1 establishes multi-enhancer networks to regulate gene expression

LDB1 establishes multi-enhancer networks to regulate gene expression

  • bioRxiv. 2024 Aug 24:2024.08.23.609430. doi: 10.1101/2024.08.23.609430.
Nicholas G Aboreden 1 2,  Jessica C Lam 1 2,  Viraat Y Goel 3 4 5,  Siqing Wang 2,  Xiaokang Wang 2,  Susannah C Midla 2,  Alma Quijano 1 2,  Cheryl A Keller 6,  Belinda M Giardine 6,  Ross C Hardison 6,  Haoyue Zhang 7,  Anders S Hansen 3 4 5,  Gerd A Blobel 1 2
Affiliations

Affiliations

  • 1 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 3 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 4 Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 5 Koch Institute for Integrative Cancer Research, Cambridge, MA, USA.
  • 6 Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, USA.
  • 7 Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China.
PMID: 39229045 DOI: 10.1101/2024.08.23.609430
Abstract

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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