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Cited by 61Genomics and Chromatin DynamicsChromatin Remodeling and CancerNuclear Structure and Function

LDB1 establishes multi-enhancer networks to regulate gene expression

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Aboreden, Nicholas G., Lam, Jessica C., Goel, Viraat Y., Wang, Siqing, Wang, Xiaokang, Midla, Susannah C., Quijano, Alma, Keller, Cheryl A. +5 more·2025·Molecular Cell
DOI 10.1016/j.molcel.2024.11.037PMC PMC11741933

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Abstract

How specific enhancer-promoter pairing is established remains mostly unclear. Besides the CTCF/cohesin machinery, few nuclear factors have been studied for a direct role in physically connecting regulatory elements. Using a murine erythroid cell model, we show via acute degradation experiments that LDB1 directly and broadly promotes connectivity among regulatory elements. Most LDB1-mediated contacts, even those spanning hundreds of kb, can form in the absence of CTCF, cohesin, or YY1 as determined using 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 aids 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 observe that loop formation and de novo LDB1 occupancy correlate and can occur independently of structural loops. Tri-C and Region Capture Micro-C reveal that LDB1 organizes multi-enhancer networks to activate transcription. These findings establish LDB1 as a driver of spatial connectivity.

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Cited by

Sorted by citations

Authors
Aboreden, N. G., Lam, J. C., Goel, V. Y., Wang, S., Wang, X., Midla, S. C., Quijano, A., Keller, C. A., Giardine, B. M., Hardison, R. C., Zhang, H., Hansen, A. S., & Blobel, G. A.
Affiliations
  • Children's Hospital of Philadelphia (US)
  • Broad Institute (US)
  • Pennsylvania State University (US)
  • Shenzhen Bay Laboratory (CN)
Corresponding author
Blobel, Gerd A.
ORCID
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2025-01
Volume
85
Issue
2
Pages
376-393.e9
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/j.molcel.2024.11.037
PMC
PMC11741933
OpenAlex
W4405737555
Cited by
61
References
22
Citations by year
2026: 24 · 2025: 32 · 2024: 5
FWCI
8.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • ScholarlyCommons (University of Pennsylvania) (submittedVersion)
Funders
  • National Institutes of Health
  • National Natural Science Foundation of China (321004422, MD27K64M19, U01DK127405)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
LDB1, chromatin looping, CTCF, YY1, nuclear organization, transcriptional activation

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